bims-meladi Biomed News
on Melanocytes in development and disease
Issue of 2021–08–29
sixty-five papers selected by
Farah Jaber-Hijazi, University of the West of Scotland
  1. Regression of nevi, vitiligo-like depigmentation and halo phenomenon may indicate response to immunotherapy and targeted therapy in melanoma.
  2. The Role of Glycosylation in Melanoma Progression.
  3. Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.
  4. Re: Prognostic factors for early stage of melanoma.
  5. Current Landscape and Open Questions on Adjuvant Therapies in Melanoma.
  6. Aberrant Expression of Immunohistochemical Markers in Malignant Melanoma: A Review.
  7. Treatment of Advanced Metastatic Melanoma.
  8. Antimelanoma activities of chimeric thiazole-androstenone derivatives.
  9. A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma.
  10. Epidemiology and Risk Factors of Melanoma: A Review.
  11. Gelsolin Contributes to the Motility of A375 Melanoma Cells and This Activity Is Mediated by the Fibrous Extracellular Matrix Protein Profile.
  12. Novel Prognostic Immunohistochemical Markers in Uveal Melanoma-Literature Review.
  13. Elucidation of Melanogenesis-Associated Signaling Pathways Regulated by Argan Press Cake in B16 Melanoma Cells.
  14. PRAME immunohistochemistry is useful in the diagnosis of oral malignant melanoma.
  15. Identification of Six Autophagy-Related-lncRNA Prognostic Biomarkers in Uveal Melanoma.
  16. Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma.
  17. Peroxidasin protein expression and enzymatic activity in metastatic melanoma cell lines are associated with invasive potential.
  18. Plasma Exosome-Derived SENP1 May Be a Potential Prognostic Predictor for Melanoma.
  19. METTL3-induced UCK2 m6A hypermethylation promotes melanoma cancer cell metastasis via the WNT/β-catenin pathway.
  20. Expression of the cancer stem cell marker OCT4 is associated with worse prognosis and survival in cutaneous melanoma.
  21. Effects of RNA methylation N6-methyladenosine regulators on malignant progression and prognosis of melanoma.
  22. Expression of Alternative Splice Variants of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-4 in Normoxic and Hypoxic Melanoma Cells.
  23. Limitation of Using Ultrasonography After Positive Sentinel Lymph Node Biopsy in a Patient with Melanoma in the Detection of Lymph Node Metastasis.
  24. Low-Heterogeneity Melanomas Are More Immunogenic and Less Aggressive.
  25. Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.
  26. TCF21 regulates miR-10a-5p/LIN28B signaling to block the proliferation and invasion of melanoma cells.
  27. The Role of LncRNAs in Uveal Melanoma.
  28. Computer-Aided Diagnosis Algorithm for Classification of Malignant Melanoma Using Deep Neural Networks.
  29. TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase.
  30. The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells.
  31. A Novel 8-Gene Prognostic Signature for Survival Prediction of Uveal Melanoma.
  32. In Uveal Melanoma, Angiopoietin-2 but Not Angiopoietin-1 Is Increased in High-Risk Tumors, Providing a Potential Druggable Target.
  33. Epigenetic Regulation in Melanoma: Facts and Hopes.
  34. Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.
  35. Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma.
  36. The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma.
  37. Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis.
  38. Gene expression profiling in melanoma: A view from the clinic.
  39. Cell Adhesion Molecules in Normal Skin and Melanoma.
  40. A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine.
  41. Inhibition of spindle and kinetochore associated complex subunit 3 suppresses the proliferation and invasion and induced the apoptosis of cutaneous melanoma by affecting the PI3K/Akt pathway.
  42. Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights.
  43. Melanocyte progenitor cells reside in human subcutaneous adipose tissue.
  44. EVI2B Is a New Prognostic Biomarker in Metastatic Melanoma with IFNgamma Associated Immune Infiltration.
  45. CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma.
  46. hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote its translation in stressed melanoma cells.
  47. Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management.
  48. Molecular Changes Induced in Melanoma by Cell Culturing in 3D Alginate Hydrogels.
  49. Unraveling the Wide Spectrum of Melanoma Biomarkers.
  50. Metastatic Cutaneous Melanoma in a White African Lioness (Panthera leo).
  51. Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect.
  52. Melanoma: Staging and Follow-Up.
  53. GNAI2 Promotes Proliferation and Decreases Apoptosis in Rabbit Melanocytes.
  54. TGF-β Increases MFGE8 Production in Myeloid-Derived Suppressor Cells to Promote B16F10 Melanoma Metastasis.
  55. Co-expression of MTH1 and PMS2 is associated with advanced disease and disease progression after therapy in melanoma.
  56. Dedifferentiated melanoma with MDM2 gene amplification mimicking dedifferentiated liposarcoma.
  57. Validity and feasibility of the self-assessment vitiligo extent score among Egyptian patients.
  58. The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent-DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors.
  59. Phylogenetic Analysis of Core Melanin Synthesis Genes Provides Novel Insights Into the Molecular Basis of Albinism in Fish.
  60. A Clinicopathological Analysis of Melanocytic Nevi: A Retrospective Series.
  61. Morus alba Root Extract Induces the Anagen Phase in the Human Hair Follicle Dermal Papilla Cells.
  62. Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor.
  63. PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ-DNMT1 Interactions in the Genome.
  64. Cathepsin L, a Target of Hypoxia-Inducible Factor-1-α, Is Involved in Melanosome Degradation in Melanocytes.
  65. Catabolism of lysosome-related organelles in color-changing spiders supports intracellular turnover of pigments.
  1. Melanoma Res. 2021 Aug 23.
    Regression of nevi, vitiligo-like depigmentation and halo phenomenon may indicate response to immunotherapy and targeted therapy in melanoma.
    Eleonora Farinazzo, Enrico Zelin, Marina Agozzino, Giovanni Papa, Maria Antonietta Pizzichetta, Nicola di Meo, Iris Zalaudek.
      We present two patients with stage IV melanoma, the first with BRAF wild-type melanoma with multiple visceral metastases treated with immunotherapy (pembrolizumab) and the second with BRAFV600E melanoma with subcutaneous and lymph nodes metastasis treated with BRAF and MEK-inhibitors (dabrafenib/trametinib). Already after the second cycle of immunotherapy, the first patient developed a diffuse regression of nevi, perceptible only with the use of dermoscopy and 3 months later a clinically evident poliosis of the eyebrows. The second patient, treated with dabrafenib/trametinib, developed small areas of leukoderma on his chest and white halos around nevi with a dermoscopic globular or structureless pattern. Both observations are suggestive for an immune reaction against melanocytic cells, which is further supported by the complete response to systemic therapy in both patients. It has been demonstrated that the development of vitiligo-like depigmentation during immunotherapy is associated with a better prognosis; in our patient, the phenomenon of poliosis appeared much later than the dermoscopic presence of regression among his nevi, suggesting that the latter may be an early sign (along with vitiligo-like phenomena) of good response to immunotherapy. On the other hand, the development of halo nevi and leukoderma during treatment with BRAF/MEK-inhibitors, suggests that not only immunotherapy but also targeted therapy may induce an immunologic response against melanoma and nevi, again indicative of a favorable prognosis. More data are needed to confirm these findings; however, they indicate that dermatologists should be involved in the follow-up of patients with melanoma, both in studies and clinical practice.
    DOI:  https://doi.org/10.1097/CMR.0000000000000776
  2. Cells. 2021 Aug 19. pii: 2136. [Epub ahead of print]10(8):
    The Role of Glycosylation in Melanoma Progression.
    Chiara De Vellis, Silvia Pietrobono, Barbara Stecca.
      Malignant melanoma is the most aggressive form of skin cancer, which originates from the malignant transformation of melanocytes, the melanin-producing cells of the skin. Melanoma progression is typically described as a stepwise process in which metastasis formation ensues late during disease. A large body of evidence has shown that the accumulation of genetic and epigenetic alterations drives melanoma progression through the different steps. Mortality in melanoma is associated with metastatic disease. Accordingly, early-stage melanoma can be cured in the majority of cases by surgical excision, while late-stage melanoma is a highly lethal disease. Glycosylation is a post-translational modification that involves the transfer of glycosyl moieties to specific amino acid residues of proteins to form glycosidic bonds through the activity of glycosyltransferases. Aberrant glycosylation is considered a hallmark of cancer as it occurs in the majority of tumor types, including melanoma. The most widely occurring glycosylation changes in melanoma are represented by sialylation, fucosylation, and N- and I-glycan branching. In this review, we discuss the role of glycosylation in melanoma and provide insights on the mechanisms by which aberrant glycosylation promotes melanoma progression through activation of invasion and metastasis, immune evasion and cell proliferation.
    Keywords:  fucosylation; glycan branching; glycosylation; immune evasion; melanoma; metastasis; sialylation
    DOI:  https://doi.org/10.3390/cells10082136
  3. Future Oncol. 2021 Aug 25.
    Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.
    Francesca Comito, Paola Valeria Marchese, Angela Dalia Ricci, Nastassja Tober, Chiara Peterle, Francesca Sperandi, Barbara Melotti.
      Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.
    Keywords:  chemotherapy; immTACs; immunotherapy; liver-directed; locoregional therapy; metastatic uveal melanoma; ocular melanoma; targeted therapy; tebentafusp; uveal melanoma
    DOI:  https://doi.org/10.2217/fon-2021-0318
  4. Eur J Cancer. 2021 Aug 19. pii: S0959-8049(21)00477-9. [Epub ahead of print]
    Re: Prognostic factors for early stage of melanoma.
    Tomoyuki Kawada.
      
    Keywords:  Early stage; Melanoma; Prognosis; Relapse; Risk assessment
    DOI:  https://doi.org/10.1016/j.ejca.2021.07.020
  5. Dermatol Pract Concept. 2021 Jul;11(Suppl 1): e2021165S
    Current Landscape and Open Questions on Adjuvant Therapies in Melanoma.
    Vincenzo De Falco, Stefania Napolitano, Luigi Pio Guerrera, Teresa Troiani.
      Melanoma is a form of skin cancer that is frequently diagnosed at early stages. In most cases, surgical resection is curative. In case of thicker melanomas (> pT1b) without clinical or instrumental evidence of metastasis, a sentinel lymph node biopsy is recommended for staging purposes. If the lymph nodes are the only site of disease (macroscopic or microscopic> 1mm), configuring stage III, the international guidelines recommend the use of adjuvant therapy with checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapies (dabrafenib plus trametinib). These drugs have shown a significant increase in recurrence-free survival, although some doubts and open questions remain. Specifically, none of the available treatments has shown a clear benefit in the overall survival rates, the advantages they give in stage IIIA are not well known, and finally there are still no prospective clinical studies identifying the best approach to continue the therapeutic process in case of relapse. Furthermore, there are new opportunities opening up with the upcoming results of the neoadjuvant trials that could revolutionize the treatment of clinically evident stage III melanoma.
    Keywords:  adjuvant therapy; locoregional melanoma; stage III melanoma
    DOI:  https://doi.org/10.5826/dpc.11S1a165S
  6. Dermatopathology (Basel). 2021 Aug 03. 8(3): 359-370
    Aberrant Expression of Immunohistochemical Markers in Malignant Melanoma: A Review.
    Elie Saliba, Jag Bhawan.
      Immunohistochemical stains are increasingly used to aid in the diagnosis of malignant melanoma, especially when the differentiation of the tumor is unclear based on examination with hematoxylin and eosin. However, aberrant expression of non-melanocytic markers has been reported in melanomas, which can sometimes be further complicated by the loss of conventional melanocytic markers. This review aims to summarize available data regarding unusual staining patterns in primary and metastatic malignant melanoma. It also raises awareness of the potential pitfalls and highlights the importance of appropriate use and interpretation of broad immunohistochemical markers in the context of clinical and histopathologic findings to facilitate the diagnosis of atypical cases of malignant melanoma.
    Keywords:  aberrant expression; immunohistochemistry; malignant melanoma; melanocytic markers
    DOI:  https://doi.org/10.3390/dermatopathology8030040
  7. Dermatol Pract Concept. 2021 Jul;11(Suppl 1): e2021164S
    Treatment of Advanced Metastatic Melanoma.
    Pietro Quaglino, Paolo Fava, Luca Tonella, Marco Rubatto, Simone Ribero, Maria Teresa Fierro.
      The introduction in clinical practice of new drug compounds both targeted therapies anti-BRAF and checkpoint inhibitors have largely improved our potential to manage advanced metastatic melanoma patients. This has led to a significant improvement in terms of response rates and particularly in the overall survival (OS). The long-term results of trials with follow-up data of patients treated with targeted or immunotherapies reported median OS rates around 24 months, with 5-year survival rates around 35-40%. As to the drugs currently available and reimbursed by the Italian National Health System, 3 combinations of anti-BRAF/anti-MEK inhibitors are available (dabrafenib/trametinib, vemurafenib/cobimetinib and the most recently introduced encorafenib/binimetinib). As for checkpoint inhibitors, first line immunotherapy is represented by anti-PD1 blockers (nivolumab and pembrolizumab), whilst the anti-CTLA-4 ipilimumab can be used as second line immunotherapy. The decision-making factors that define the best treatment approach in stage IV patients with metastatic melanoma include the mutation pattern, performance status, high/low tumor load, brain metastases, progression pattern (low/fast), and availability of clinical trials. This review will analyze the current therapeutic tools adopted for the treatment of metastatic melanoma patients. It will then focus on the latest results obtained by novel treatments (checkpoint inhibitors and targeted therapies) which can be used in the clinical daily practice.
    Keywords:  Metastatic melanoma treatment; anti-PD1; metastatic melanoma survival; response rate; target therapy
    DOI:  https://doi.org/10.5826/dpc.11S1a164S
  8. R Soc Open Sci. 2021 Aug;8(8): 210395
    Antimelanoma activities of chimeric thiazole-androstenone derivatives.
    Steven A Chambers, Mathew Newman, Melissa M Frangie, Alena V Savenka, Alexei G Basnakian, Mohammad A Alam.
      The discovery of chimeric anti-melanoma agents is reported. These molecules are potent growth suppressors of melanoma cells in vitro with growth inhibition of 50% (GI50) values as low as 1.32 µM. Compounds were more toxic to melanoma cells in vitro than commonly used anti-melanoma agent dacarbazine as measured by TUNEL assay. They induced both caspase-independent apoptosis evident by colocalization of TUNEL with endonuclease G (EndoG) and caspase-mediated apoptosis measured by colocalization of TUNEL with caspase-activated DNase (CAD). In addition, compounds 3 and 5 strongly induced oxidative injury to melanoma cells as measured by TUNEL colocalization with heme oxygenase-1 (HO1). Dacarbazine induced only caspase-independent apoptosis, which may explain why it is less cytotoxic to melanoma cells than compounds 3, 4 and 5.
    Keywords:  TUNEL assay; androstenone; apoptosis; flow cytometry; melanoma; thiazole
    DOI:  https://doi.org/10.1098/rsos.210395
  9. Front Genet. 2021 ;12 697043
    A Ferroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Cutaneous Melanoma.
    Congcong Xu, Hao Chen.
       Background: Cutaneous melanoma is a common but aggressive tumor. Ferroptosis is a recently discovered cell death with important roles in tumor biology. Nevertheless, the prognostic power of ferroptosis-linked genes remained unclear in cutaneous melanoma.
    Methods: Cutaneous melanoma patients of TCGA (The Cancer Genome Atlas) were taken as the training cohort while GSE65904 and GSE22153 as the validation cohorts. Multifactor Cox regression model was used to build a prognostic model, and the performance of the model was assessed. Functional enrichment and immune infiltration analysis were used to clarify the mechanisms.
    Results: A five ferroptosis-linked gene predictive model was developed. ALOX5 and GCH1 were illustrated as independent predictive factors. Functional assessment showed enriched immune-linked cascades. Immune infiltrating analysis exhibited the distinct immune microenvironment.
    Conclusion: Herein, a novel ferroptosis-related gene prognostic model was built in cutaneous melanoma. This model could be used for prognostic prediction, and maybe helpful for the targeted and immunotherapies.
    Keywords:  cutaneous melanoma; ferroptosis; gene model; immune; prognosis
    DOI:  https://doi.org/10.3389/fgene.2021.697043
  10. Dermatol Pract Concept. 2021 Jul;11(Suppl 1): e2021161S
    Epidemiology and Risk Factors of Melanoma: A Review.
    Claudio Conforti, Iris Zalaudek.
      We are currently witnessing a worldwide increase in the incidence of melanoma. Incidence in Europe is about 25 cases per 100,000 population, while in Australia it reaches a rate of 60 new cases per 100,000. While the epidemiological curves of the 1980's and 1990's suggested an increase in the incidence of melanoma across all age groups, the last 10 years' data indicates a 5% reduction in the incidence of thin melanoma in young individuals aged between 15 and 24. This suggests a positive impact of primary prevention campaigns [1-2]. The risk factors associated with melanoma are different and multifactorial: on one hand there is a genetic predisposition, as evidenced by the increased risk in patients with dysplastic nevus syndrome, with familial melanoma or familial melanoma syndromes; on the other hand, the unprotected interaction between UV rays and phototypes I-II increases the risk of developing melanoma, especially in case of sunburns in pediatric age. This review aims to summarize melanoma epidemiology and risk factors.
    Keywords:  Melanoma; epidemiology; nevi; risk factors
    DOI:  https://doi.org/10.5826/dpc.11S1a161S
  11. Cells. 2021 Jul 21. pii: 1848. [Epub ahead of print]10(8):
    Gelsolin Contributes to the Motility of A375 Melanoma Cells and This Activity Is Mediated by the Fibrous Extracellular Matrix Protein Profile.
    Ewa Mazurkiewicz, Aleksandra Makowiecka, Ewa Mrówczyńska, Iryna Kopernyk, Dorota Nowak, Antonina Joanna Mazur.
      Skin melanocytes reside on the basement membrane (BM), which is mainly composed of laminin, collagen type IV, and proteoglycans. For melanoma cells, in order to invade into the skin, melanocytes must cross the BM. It has been reported that changes in the composition of the BM accompany melanocytes tumorigenesis. Previously, we reported high gelsolin (GSN)-an actin-binding protein-levels in melanoma cell lines and GSN's importance for migration of A375 cells. Here we investigate whether melanoma cells migrate differently depending on the type of fibrous extracellular matrix protein. We obtained A375 melanoma cells deprived of GSN synthesis and tested their migratory properties on laminin, collagens type I and IV, fibronectin, and Matrigel, which resembles the skin's BM. We applied confocal and structured illuminated microscopy (SIM), gelatin degradation, and diverse motility assays to assess GSN's influence on parameters associated with cells' ability to protrude. We show that GSN is important for melanoma cell migration, predominantly on laminin, which is one of the main components of the skin's BM.
    Keywords:  CRISPR/Cas9(D10A) technique; Matrigel; SIM; actin cytoskeleton; collagen; extracellular matrix (ECM); fibronectin; gelsolin (GSN); invasion; laminin; melanoma; motility
    DOI:  https://doi.org/10.3390/cells10081848
  12. Cancers (Basel). 2021 Aug 10. pii: 4031. [Epub ahead of print]13(16):
    Novel Prognostic Immunohistochemical Markers in Uveal Melanoma-Literature Review.
    Malgorzata Gajdzis, Radoslaw Kaczmarek, Pawel Gajdzis.
      Uveal melanoma is the most common primary intraocular neoplasm in adults. As there are currently no effective methods of treating the disease in the metastatic stage, there is a need to search for new prognostic factors that would enable a reliable assessment of the patient's condition and constitute a possible therapeutic target. In this review, we have prepared the results of English-language studies on new prognostic factors determined with immunohistochemical methods. We found 64 articles in which the expression of various proteins was associated in a statistically significant manner with the histopathological and clinical prognostic factors identified by AJCC. The results of our work clearly show that the biology of uveal melanoma is extraordinarily complex. Numerous studies have shed new light on the complexity of the processes involved in the development of this cancer. Moreover, a careful analysis of the expression of individual proteins may allow the identification of homogeneous groups of patients requiring different treatment regimens.
    Keywords:  immunohistochemistry; prognostic factors; proteins; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13164031
  13. Nutrients. 2021 Aug 04. pii: 2697. [Epub ahead of print]13(8):
    Elucidation of Melanogenesis-Associated Signaling Pathways Regulated by Argan Press Cake in B16 Melanoma Cells.
    Thouria Bourhim, Myra O Villareal, Chemseddoha Gadhi, Hiroko Isoda.
      The beneficial effect on health of argan oil is recognized worldwide. We have previously reported that the cake that remains after argan oil extraction (argan press-cake or APC) inhibits melanogenesis in B16 melanoma cells in a time-dependent manner without cytotoxicity. In this study, the global gene expression profile of B16 melanoma cells treated with APC extract was determined in order to gain an understanding of the possible mechanisms of action of APC. The results suggest that APC extract inhibits melanin biosynthesis by down-regulating microphthalmia-associated transcription factor (Mitf) and its downstream signaling pathway through JNK signaling activation, and the inhibition of Wnt/β-catenin and cAMP/PKA signaling pathways. APC extract also prevented the transport of melanosomes by down-regulating Rab27a expression. These results suggest that APC may be an important natural skin whitening product and pharmacological agent used for clinical treatment of pigmentary disorders.
    Keywords:  JNK; MITF; Wnt/β-catenin; argan press-cake; cAMP/PKA; microarray analysis
    DOI:  https://doi.org/10.3390/nu13082697
  14. Oral Oncol. 2021 Aug 24. pii: S1368-8375(21)00606-0. [Epub ahead of print] 105500
    PRAME immunohistochemistry is useful in the diagnosis of oral malignant melanoma.
    Daniel Hovander, Joshua Allen, Dolphine Oda, Ata S Moshiri.
       OBJECTIVES: While the incidence of cutaneous melanoma has dramatically increased in recent years, oral malignant melanoma (OMM) remains a rare form of noncutaneous melanoma with poor survival. PRAME (PReferentially expressed Antigen in MElanoma) is reported to have diagnostic and some prognostic utility in cutaneous melanomas and some head and neck malignancies. We sought to explore the diagnostic utility of PRAME in OMM.
    METHODS: A total of ten specimens from eight unique cases of OMM were identified from the Oral Pathology Biopsy Service (OPBS) at University of Washington School of Dentistry between 2005 and 2019. For all cases, standard histology and immunohistochemistry stains were performed, including a stain against PRAME. The diagnoses were reviewed and confirmed by two pathologists. Clinical and epidemiologic features were described.
    RESULTS: Patient ages ranged from 55 to 82. The group consisted of five males and three females. All eight cases were located on the hard palate. Six cases represented invasive melanoma while two were early melanoma in situ. PRAME immunohistochemistry was successfully performed on seven of eight cases: six were positive (86%), one was negative (14%) and one case lacked sufficient tissue for staining.
    CONCLUSIONS: Our results suggest that PRAME immunohistochemistry may be useful in the diagnosis of OMM, including early melanoma in situ. Further studies with clinical follow-up and a larger number of cases are needed to explore prognostic value as well as the ability to distinguish between benign, intermediate and malignant melanocytic proliferations of the oral cavity.
    Keywords:  In situ mucosal melanoma; OMM; Oral malignant melanoma; PRAME
    DOI:  https://doi.org/10.1016/j.oraloncology.2021.105500
  15. Dis Markers. 2021 ;2021 2401617
    Identification of Six Autophagy-Related-lncRNA Prognostic Biomarkers in Uveal Melanoma.
    Yao Chen, Lu Chen, Jinwei Wang, Jia Tan, Sha Wang.
      Currently, no autophagy-related long noncoding RNA (lncRNA) has been reported to predict the prognosis of uveal melanoma patients. Our study screened for autophagy-related lncRNAs in 80 samples downloaded from The Cancer Genome Atlas (TCGA) database through lncRNA-mRNA coexpression. We used univariate Cox to further filter the lncRNAs. Multivariate Cox regression and LASSO regression were applied to construct an autophagy-associated lncRNA predictive model and calculate the risk score. Clinical risk factors were validated using Cox regression to determine whether they were independent prognostic indicators. Functional enrichment was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The model was built with six predictive autophagy-associated lncRNAs and clustered uveal melanoma patients into high- and low-risk groups. The risk score of our model was a significant independent prognostic factor (hazard ratio = 1.0; p < 0.001). Moreover, these six lncRNAs were significantly concentrated in the biological pathways of cytoplasmic component recycling, energy metabolism, and apoptosis. Thus, the six autophagy-associated lncRNAs are potential molecular biomarkers and treatment targets for uveal melanoma patients.
    DOI:  https://doi.org/10.1155/2021/2401617
  16. Dermatol Pract Concept. 2021 Jul;11(Suppl 1): e2021163S
    Evolution of the Clinical, Dermoscopic and Pathologic Diagnosis of Melanoma.
    Harald Kittler.
      The conventional narrative states that the steadily rising incidence of melanoma among fair-skinned Caucasian populations during the last decades is caused by excessive UV-exposure. There is, however, no doubt that other factors had a significant impact on the rising incidence of melanoma. Pre-1980s the clinical diagnosis of melanoma was based on gross criteria such as ulceration or bleeding. Melanomas were often diagnosed in advanced stages when the prognosis was grim. In the mid-1980s education campaigns such as the propagation of the ABCD criteria, which addressed health care professionals and the public alike, shifted the focus towards early recognition. Dermatoscopy, which became increasingly popular in the mid-1990s, improved the accuracy for the diagnosis of melanoma in comparison to inspection with the unaided eye, especially for flat and small lesions lacking ABCD criteria. At the same time, pathologists began to lower their thresholds, particularly for the diagnosis of melanoma in situ. The melanoma epidemic that followed was mainly driven by an increase in the number of in situ or microinvasive melanomas. In a few decades, the landscape shifted from an undercalling to an overcalling of melanomas, a development that is now met with increased criticism. The gold standard of melanoma diagnosis is still conventional pathology, which is faced with low to moderate interobserver agreement. New insights in the molecular landscape of melanoma did not translate into techniques for the reliable diagnosis of gray zone lesions including small lesions. The aim of this review is to put our current view of melanoma diagnosis in historical context and to provide a narrative synthesis of its evolution. Based on this narrative I will provide suggestions on how to rebuild the trust in melanoma diagnosis accuracy and in the benefit of early recognition.
    Keywords:  Melanoma; dermatoscopy; dermoscopy; pathology
    DOI:  https://doi.org/10.5826/dpc.11S1a163S
  17. Redox Biol. 2021 Aug 04. pii: S2213-2317(21)00249-4. [Epub ahead of print]46 102090
    Peroxidasin protein expression and enzymatic activity in metastatic melanoma cell lines are associated with invasive potential.
    Martina Paumann-Page, Nikolaus F Kienzl, Jyoti Motwani, Boushra Bathish, Louise N Paton, Nicholas J Magon, Benjamin Sevcnikar, Paul G Furtmüller, Michael W Traxlmayr, Christian Obinger, Mike R Eccles, Christine C Winterbourn.
      Peroxidasin, a heme peroxidase, has been shown to play a role in cancer progression. mRNA expression has been reported to be upregulated in metastatic melanoma cell lines and connected to the invasive phenotype, but little is known about how peroxidasin acts in cancer cells. We have analyzed peroxidasin protein expression and activity in eight metastatic melanoma cell lines using an ELISA developed with an in-house peroxidasin binding protein. RNAseq data analysis confirmed high peroxidasin mRNA expression in the five cell lines classified as invasive and low expression in the three non-invasive cell lines. Protein levels of peroxidasin were higher in the cell lines with an invasive phenotype. Active peroxidasin was secreted to the cell culture medium, where it accumulated over time, and peroxidasin protein levels in the medium were also much higher in invasive than non-invasive cell lines. The only well-established physiological role of peroxidasin is in the formation of a sulfilimine bond, which cross-links collagen IV in basement membranes via catalyzed oxidation of bromide to hypobromous acid. We found that peroxidasin secreted from melanoma cells formed sulfilimine bonds in uncross-linked collagen IV, confirming peroxidasin activity and hypobromous acid formation. Moreover, 3-bromotyrosine, a stable product of hypobromous acid reacting with tyrosine residues, was detected in invasive melanoma cells, substantiating that their expression of peroxidasin generates hypobromous acid, and showing that it does not exclusively react with collagen IV, but also with other biomolecules.
    Keywords:  Bromotyrosine; Collagen IV cross-linking; Hypobromous acid; Metastatic melanoma; Peroxidasin
    DOI:  https://doi.org/10.1016/j.redox.2021.102090
  18. Front Oncol. 2021 ;11 685009
    Plasma Exosome-Derived SENP1 May Be a Potential Prognostic Predictor for Melanoma.
    Hejuan Hu, Bai Ling, Yuhan Shi, Haohao Wu, Bingying Zhu, Yiling Meng, Guo-Ming Zhang.
       Objective: To evaluate plasma exosome-derived SUMO-specific protease (SENP)1 levels and assess their prognostic value in melanoma.
    Patients and Methods: We extracted exosomes from the plasma of 126 melanoma patients, and identified them with transmission electron microscopy, nanoparticle tracking analysis and western blotting. The plasma exosome-derived SENP1 levels of melanoma patients and healthy controls were detected with ELISA.
    Results: Plasma exosome-derived SENP1 levels in melanoma patients were significantly upregulated than in healthy controls (P < 0.001). Plasma exosome-derived SENP1 levels in melanoma patients with tumor size >10 cm, located in the mucosa or viscera, with Clark level IV/V, with lymph node metastasis, and TNM stages IIb-IV were significantly higher than in patients in with tumor size <10 cm, located in the skin, with Clark level I-III, without lymph node metastasis, and TNM stages IIb-IV (all P < 0.05). Disease-free survival (DFS) and overall survival (OS) were worse in melanoma patients who had higher plasma exosome-derived SENP1 levels than lower plasma exosome-derived SENP1 levels (both P < 0.001). Area under the receiver operating characteristic curve (AUROC) of plasma exosome-derived SENP1 for predicting 3-year DFS of melanoma patients was 0.82 [95% confidence interval (CI): 0.74-0.88], with a sensitivity of 81.2% (95% CI: 69.9-89.6%) and specificity of 75.4% (95% CI: 62.2-85.9%). The AUROC of plasma exosome-derived SENP1 for predicting 3-year OS of melanoma patients was 0.76 (95% CI: 0.67-0.83), with a sensitivity of 95.7% (95% CI: 85.5-99.5%) and specificity of 62.0% (95% CI: 50.4-72.7%).
    Conclusions: Melanoma patients with higher plasma exosome-derived SENP1 levels had worse DFS and OS. The plasma exosome-derived SENP1 levels may be a potential prognostic predictor for 3-year DFS and 3-year OS of melanoma.
    Keywords:  SENP1; SUMO; exosomes; melanoma; prognostic predictor
    DOI:  https://doi.org/10.3389/fonc.2021.685009
  19. Ann Transl Med. 2021 Jul;9(14): 1155
    METTL3-induced UCK2 m6A hypermethylation promotes melanoma cancer cell metastasis via the WNT/β-catenin pathway.
    Hao Wu, Haochao Xu, Dongdong Jia, Tao Li, Liming Xia.
       Background: Melanoma is a highly aggressive, malignant skin tumor with a statistically high mortality rate. N6-methyladenosine (m6A) modification is involved in a variety of biological processes, including tumorigenesis. m6A modifications regulate the fate and functions of RNA, such as mRNA stability, nuclear processing, transport, localization, translation, primary microRNA (miRNA) processing, and RNA-protein interactions. Several members (including METTL3, METTL14, FTO, ALKBH5, and YTHDF2) are actively involved in a variety of human cancers. However, the basic mechanism of the involvement of uridine cytidine kinase 2 (UCK2) in melanoma metastasis has not been studied. UCK2 is upregulated in a variety of malignancies. However, the complex molecular mechanisms and therapeutic effects of UCK2 in melanoma remain unclear.
    Methods: The expression of UCK2 was evaluated by qRT-PCR. The effects of UCK2 on the biological characteristics of PC cells were investigated on the basis of loss-of-function analyses. Immunoprecipitation-qPCR (MeRIP-qPCR) was performed to identify the m6A targeted effect of UCK2 in melanoma cancer.
    Results: Based on the bioinformatics analysis in this study, up-regulation of UCK2 could be essential in melanoma cancer, and associated with poor survival. Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway.
    Conclusion: In this study, we found that m6A-METTL3 axis induced abnormal UCK2 expression plays a role in melanoma metastasis by enhancing the Wnt/β-catenin pathway, which may provide new clues for melanoma metastasis. It also provides a potential target for the prevention and treatment of melanoma.
    Keywords:  Uridine-cytidine kinase 2 (UCK2); database; m6A; melanoma cancer; metastasis
    DOI:  https://doi.org/10.21037/atm-21-2906
  20. Melanoma Res. 2021 Aug 23.
    Expression of the cancer stem cell marker OCT4 is associated with worse prognosis and survival in cutaneous melanoma.
    Constanza Thaise Xavier Silva, Vera Aparecida Saddi, Kleber Santiago Freitas E Silva, Denis Masashi Sugita, Lidia Andreu Guillo.
      Cutaneous melanoma has an aggressive clinical presentation, showing rapid rate of growth and metastatic dissemination due to the permanence of cancer stem cells. The present study was to evaluate the expression of the self-renewal regulatory factor and the clinical significance of the transcription factor OCT4 in melanoma. Melanoma tissues were stained by immunohistochemistry and the correlation between the expression of this marker was determined through clinical-pathological variables and survival outcomes. Positive expression of nuclear and cytoplasmic OCT4 was observed in 49% and 41.2% of cases, respectively. The positive expression of nuclear OCT4 in melanoma was significantly associated with prognostic factors, such as Breslow depth, Clark's level, ulceration and metastasis. Survival of patients was 56% compared to positive nuclear OCT4 expression and 94.2% when compared to the low expression of the gene. Nuclear OCT4 positive genotype indicated aggressive tumor behavior with a worse clinical outcome, which indicates OCT4 as a useful biomarker in the prognosis of melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000767
  21. Cancer Cell Int. 2021 Aug 26. 21(1): 453
    Effects of RNA methylation N6-methyladenosine regulators on malignant progression and prognosis of melanoma.
    Jinfang Liu, Zijian Zhou, Ling Ma, Chujun Li, Yu Lin, Ting Yu, Ji-Fu Wei, Lingjun Zhu, Gang Yao.
       BACKGROUND: Melanoma is an extremely aggressive type of skin cancer and experiencing a expeditiously rising mortality in a current year. Exploring new potential prognostic biomarkers and therapeutic targets of melanoma are urgently needed. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma.
    METHODS: Gene expression data and corresponding clinical informations of melanoma patients as well as sequence data of normal controls are collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Quantitative real-time PCR (qRT-PCR) analysis was carried out to detect the RNA expression of IGF2BP3 in A375 cell line, melanoma tissues, and normal tissues. Western blot, cell proliferation, and migration assays were performed to assess the ability of IGF2BP3 in A375 cell line.
    RESULTS: Differently expressed m6A regulators between tumor samples and normal samples were analyzed. A three-gene prognostic signature including IGF2BP3, RBM15B, and METTL16 was constructed, and the risk score of this signature was identified to be an independent prognostic indicator for melanoma. In addition, IGF2BP3 was verified to promote melanoma cell proliferation and migration in vitro and associate with lymph node metastasis in clinical samples. Moreover, risk score and the expression of IGF2BP3 were positively associated with the infiltrating immune cells and these hub genes made excellent potential drug targets in melanoma.
    CONCLUSION: We identified the genetic changes in m6A regulatory genes and constructed a three-gene risk signature with distinct prognostic value in melanoma. This research provided new insights into the epigenetic understanding of m6A regulators and novel therapeutic strategies in melanoma.
    Keywords:  IGF2BP35; Melanoma1; Prognostic signature3; TCGA4; m6A RNA methylation2
    DOI:  https://doi.org/10.1186/s12935-021-02163-9
  22. Int J Mol Sci. 2021 Aug 17. pii: 8848. [Epub ahead of print]22(16):
    Expression of Alternative Splice Variants of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-4 in Normoxic and Hypoxic Melanoma Cells.
    Sonia E Trojan, Paulina Dudzik, Justyna Totoń-Żurańska, Piotr Laidler, Kinga A Kocemba-Pilarczyk.
      Cancer-specific isoenzyme of phosphofructokinase II (PFKFB4), as our previous research has shown, may be one of the most important enzymes contributing to the intensification of glycolysis in hypoxic malignant melanoma cells. Although the PFKFB4 gene seems to play a crucial role in the progression of melanoma, so far there are no complete data on the expression of PFKFB4 at the isoform level and the influence of hypoxia on alternative splicing. Using RT-qPCR and semi-quantitative RT-PCR, we presented the PFKFB4 gene expression profile at the level of six isoforms described in the OMIM NCBI database in normoxic and hypoxic melanoma cells. Additionally, using VMD software, we analyzed the structure of isoforms at the protein level, concluding about the catalytic activity of individual isoforms. Our research has shown that five isoforms of PFKFB4 are expressed in melanoma cells, of which the D and F isoforms are highly constitutive, while the canonical B isoform seems to be the main isoform induced in hypoxia. Our results also indicate that the expression profile at the level of the PFKFB4 gene does not reflect the expression at the level of individual isoforms. Our work clearly indicates that the PFKFB4 gene expression profile should be definitely analyzed at the level of individual isoforms. Moreover, the analysis at the protein level allowed the selection of those isoforms whose functional validation should be performed to fully understand the importance of PFKFB4 expression in the metabolic adaptation of malignant melanoma cells.
    Keywords:  HIF-1; PFKFB4; hypoxia; isoforms; malignant melanoma
    DOI:  https://doi.org/10.3390/ijms22168848
  23. Yonago Acta Med. 2021 Aug;64(3): 315-317
    Limitation of Using Ultrasonography After Positive Sentinel Lymph Node Biopsy in a Patient with Melanoma in the Detection of Lymph Node Metastasis.
    Hiroyuki Goto, Kazunari Sugita, Osamu Yamamoto.
      Recent studies have shown that complete lymph node dissection (CLND) performed immediately did not improve the overall survival in patients with sentinel lymph node (LN)-positive melanoma. According to these results, nodal observation with ultrasonography becomes standard. However, it still has some limitations for detection of metastatic LNs. A 74-year-old woman was diagnosed with acral lentiginous melanoma of her left sole. The sentinel LN was positive for metastasis, but she refused CLND. Sixteen months after operation, ultrasonography showed an abnormal LN in the inguinal region. There was no other abnormal LNs around the LN. We resected the abnormal LN. The resected LN was black in color, and the adjacent LN that showed normal appearance in ultrasonography was also black. A recent study showed only 6.6% sensitivity in preoperative ultrasonographic detection of metastatic melanoma in a LN. We should keep in mind the limitation of ultrasonography for detection of a metastatic LN.
    Keywords:  lymph node dissection; lymph node metastasis; melanoma and ultrasonography
    DOI:  https://doi.org/10.33160/yam.2021.08.008
  24. Cancer Discov. 2019 Nov;9(11): 1483
    Low-Heterogeneity Melanomas Are More Immunogenic and Less Aggressive.
      In mouse models of melanoma, lower intratumoral heterogeneity (ITH) correlated with lower tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-144
  25. Oncogene. 2021 Aug 25.
    Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients.
    M Kathryn Leonard, Gemma S Puts, Nidhi Pamidimukkala, Gautam Adhikary, Yili Xu, Eric Kwok, Yuxin Jin, Devin Snyder, Nicolette Matsangos, Marián Novak, Anup Mahurkar, Amol C Shetty, Radomir M Slominski, Edward C De Fabo, Frances P Noonan, Chi-Ping Day, Mohammed Rigi, Andrzej T Slominski, Michelle G Webb, David W Craig, Glenn Merlino, Richard L Eckert, John D Carpten, Zarko Manojlovic, David M Kaetzel.
      Hepatocyte growth factor-overexpressing mice that harbor a deletion of the Ink4a/p16 locus (HP mice) form melanomas with low metastatic potential in response to UV irradiation. Here we report that these tumors become highly metastatic following hemizygous deletion of the Nme1 and Nme2 metastasis suppressor genes (HPN mice). Whole-genome sequencing of melanomas from HPN mice revealed a striking increase in lung metastatic activity that is associated with missense mutations in eight signature genes (Arhgap35, Atp8b4, Brca1, Ift172, Kif21b, Nckap5, Pcdha2, and Zfp869). RNA-seq analysis of transcriptomes from HP and HPN primary melanomas identified a 32-gene signature (HPN lung metastasis signature) for which decreased expression is strongly associated with lung metastatic potential. Analysis of transcriptome data from The Cancer Genome Atlas revealed expression profiles of these genes that predict improved survival of patients with cutaneous or uveal melanoma. Silencing of three representative HPN lung metastasis signature genes (ARRDC3, NYNRIN, RND3) in human melanoma cells resulted in increased invasive activity, consistent with roles for these genes as mediators of the metastasis suppressor function of NME1 and NME2. In conclusion, our studies have identified a family of genes that mediate suppression of melanoma lung metastasis, and which may serve as prognostic markers and/or therapeutic targets for clinical management of metastatic melanoma.
    DOI:  https://doi.org/10.1038/s41388-021-01998-w
  26. PLoS One. 2021 ;16(8): e0255971
    TCF21 regulates miR-10a-5p/LIN28B signaling to block the proliferation and invasion of melanoma cells.
    Haijun Zhu, Mengshi Kang, Xinping Bai.
       BACKGROUND AND AIM: Some research has suggested that miRNA-10a (miR-10a-5p) had an inhibitory function in proliferation and invasion of cancers. Whereas the role of miR-10a-5p in melanoma has not been fully explored. This study aims to confirm LIN28B as the targeted gene of miR-10a-5p which was explored in melanoma cells. In addition, upstream regulatory molecule of miR-10a-5p was also investigated in melanoma cells.
    METHODS: Real-time Quantitative polymerase chain reaction (RT-qPCR) was adopted to analyze miR-10a-5p expression level in melanoma and the normal human epidermal melanocyte cells. Several biological assays were performed to evaluate miR-10a-5p influences on cell proliferation, migration and invasion ability in A375 and B16-F10 cells. Gene prediction of miRNA targeting and a dual luciferase assay were applied to assess miR-10a-5p-targeted LIN28B. Western blot assessed the impacts of miR-10a-5p on the protein expression of LIN28B. Western blot analyzed the TCF21 effects on the expression of LIN28B and RT-qPCR assessed the influence of TCF21 on the expression level of miRNA-10a. In addition, Chromatin Immunoprecipitation (ChIP) Assay and JASPAR databases were employed to explore the regulatory relationship between TCF21 and miR-10a-5p.
    RESULTS: We discovered that miR-10a-5p expression was lower in melanoma cells and high expression of miR-10a-5p suppressed the proliferation, migration and invasion abilities of melanoma cells. We also discovered that miR-10a-5p targeted the LIN28B mRNA 3'UTR area and diminished LIN28B protein expression. We found that LIN28B expression was strongly decreased by TCF21 upregulation in the two melanoma cells. The qRT-PCR assay showed that miR-10a-5p expression level was obviously boosted by increased TCF21 expression. The results also demonstrated that TCF21 directly regulated miR-10a-5p at transcript levels.
    CONCLUSION: TCF21 induced miRNA-10a targeting LIN28B could affect the progression and growth of melanoma.
    DOI:  https://doi.org/10.1371/journal.pone.0255971
  27. Cancers (Basel). 2021 Aug 11. pii: 4041. [Epub ahead of print]13(16):
    The Role of LncRNAs in Uveal Melanoma.
    Paula Milán-Rois, Anan Quan, Frank J Slack, Álvaro Somoza.
      Uveal melanoma (UM) is an intraocular cancer tumor with high metastatic risk. It is considered a rare disease, but 90% of affected patients die within 15 years. Non-coding elements (ncRNAs) such as long non-coding RNAs (lncRNAs) have a crucial role in cellular homeostasis maintenance, taking part in many critical cellular pathways. Their deregulation, therefore, contributes to the induction of cancer and neurodegenerative and metabolic diseases. In cancer, lncRNAs are implicated in apoptosis evasion, proliferation, invasion, drug resistance, and other roles because they affect tumor suppressor genes and oncogenes. For these reasons, lncRNAs are promising targets in personalized medicine and can be used as biomarkers for diseases including UM.
    Keywords:  cancer; diagnosis; epigenetics; lncRNA; noncoding RNA; therapy; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13164041
  28. Sensors (Basel). 2021 Aug 18. pii: 5551. [Epub ahead of print]21(16):
    Computer-Aided Diagnosis Algorithm for Classification of Malignant Melanoma Using Deep Neural Networks.
    Chan-Il Kim, Seok-Min Hwang, Eun-Bin Park, Chang-Hee Won, Jong-Ha Lee.
      Malignant melanoma accounts for about 1-3% of all malignancies in the West, especially in the United States. More than 9000 people die each year. In general, it is difficult to characterize a skin lesion from a photograph. In this paper, we propose a deep learning-based computer-aided diagnostic algorithm for the classification of malignant melanoma and benign skin tumors from RGB channel skin images. The proposed deep learning model constitutes a tumor lesion segmentation model and a classification model of malignant melanoma. First, U-Net was used to classify skin lesions in dermoscopy images. We implement an algorithm to classify malignant melanoma and benign tumors using skin lesion images and expert labeling results from convolutional neural networks. The U-Net model achieved a dice similarity coefficient of 81.1% compared to the expert labeling results. The classification accuracy of malignant melanoma reached 80.06%. As a result, the proposed AI algorithm is expected to be utilized as a computer-aided diagnostic algorithm to help early detection of malignant melanoma.
    Keywords:  computer aided diagnosis; convolutional neural network; malanoma
    DOI:  https://doi.org/10.3390/s21165551
  29. Int J Mol Sci. 2021 Aug 04. pii: 8359. [Epub ahead of print]22(16):
    TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase.
    Loretta Ferrera, Raffaella Barbieri, Cristiana Picco, Paolo Zuccolini, Alessia Remigante, Sara Bertelli, Maria Rita Fumagalli, Giovanni Zifarelli, Caterina A M La Porta, Paola Gavazzo, Michael Pusch.
      Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline-a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc-a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole-two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.
    Keywords:  TRP channels; intracellular calcium; melanoma; oxidative stress; potassium channels
    DOI:  https://doi.org/10.3390/ijms22168359
  30. Pharmaceuticals (Basel). 2021 Aug 20. pii: 820. [Epub ahead of print]14(8):
    The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells.
    Angéla Takács, Zsófia Szász, Márton Kalabay, Péter Bárány, Antal Csámpai, Hargita Hegyesi, Orsolya Láng, Eszter Lajkó, László Kőhidai.
      Combination antitumor treatments are essential parts of modern tumor therapy as-compared to monotherapies-(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.
    Keywords:  TIC10; antitumor efficacy; bortezomib; combination therapy; melanoma
    DOI:  https://doi.org/10.3390/ph14080820
  31. Anal Cell Pathol (Amst). 2021 ;2021 6693219
    A Novel 8-Gene Prognostic Signature for Survival Prediction of Uveal Melanoma.
    Zhongjun Tang, Kebo Cai.
       Background: Uveal melanoma (UM) has favorable local tumor control, but once metastasis develops, the prognosis is rather poor. Thus, it is urgent to develop metastasis predicting markers.
    Objective: Our study investigated a novel gene expression-based signature in predicting metastasis for patients with UM.
    Methods: In the discovery phase, 63 patients with UM from GEO data set GSE22138 were analyzed using the Weighted Correlation Network Analysis (WGCNA) to identify metastasis-related hub genes. The Least Absolute Shrinkage and Selection Operator (Lasso) Cox regression was used to select candidate genes and build a gene expression signature. In the validation phase, the signature was validated in The Cancer Genome Atlas database.
    Results: Forty-one genes were identified as hub genes of metastasis by WGCNA. After the Lasso Cox regression analysis, eight genes including RPL10A, EIF1B, TIPARP, RPL15, SLC25A38, PHLDA1, TFDP2, and MEGF10 were highlighted as candidate predictors. The gene expression signature for UM (UMPS) could independently predict MFS by univariate and multivariate Cox regression analysis. Incorporating UMPS increased the AUC of the traditional clinical model. In the validation cohort, UMPS performed well in predicting the MFS of UM patients.
    Conclusions: UMPS, an eight-gene-based signature, is useful in predicting prognosis for patients with UM.
    DOI:  https://doi.org/10.1155/2021/6693219
  32. Cancers (Basel). 2021 Aug 07. pii: 3986. [Epub ahead of print]13(16):
    In Uveal Melanoma, Angiopoietin-2 but Not Angiopoietin-1 Is Increased in High-Risk Tumors, Providing a Potential Druggable Target.
    Anna M W Ten Voorde, Annemijn P A Wierenga, Rogier J Nell, Pieter A van der Velden, Gregorius P M Luyten, Robert M Verdijk, Martine J Jager.
      Uveal melanoma (UM) metastasize haematogeneously, and tumor blood vessel density is an important prognostic factor. We hypothesized that proangiogenic factors such as angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), two targetable cytokines, might play a role in tumor development and metastatic behavior. mRNA levels of ANG-1 and ANG-2 were determined in 64 tumors using an Illumina HT-12 v4 mRNA chip and compared to clinical, pathologic, and genetic tumor parameters. Tissue expression was also determined by immunohistochemistry (IHC). Samples of aqueous humor were collected from 83 UM-containing enucleated eyes and protein levels that were determined in a multiplex proximity extension assay. High tissue gene expression of ANG-2, but not of ANG-1, was associated with high tumor thickness, high largest basal diameter, involvement of the ciliary body, and with UM-related death (ANG-2 mRNA p < 0.001; ANG-2 aqueous protein p < 0.001). The presence of the ANG-2 protein in aqueous humor correlated with its mRNA expression in the tumor (r = 0.309, p = 0.03). IHC showed that ANG-2 was expressed in macrophages as well as tumor cells. The presence of ANG-2 in the tumor and in aqueous humor, especially in high-risk tumors, make ANG-2 a potential targetable cytokine in uveal melanoma.
    Keywords:  angiogenesis; eye disease; inflammation; oncology; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13163986
  33. Cells. 2021 Aug 11. pii: 2048. [Epub ahead of print]10(8):
    Epigenetic Regulation in Melanoma: Facts and Hopes.
    Emilio Francesco Giunta, Gianluca Arrichiello, Marcello Curvietto, Annalisa Pappalardo, Davide Bosso, Mario Rosanova, Anna Diana, Pasqualina Giordano, Angelica Petrillo, Piera Federico, Teresa Fabozzi, Sara Parola, Vittorio Riccio, Brigitta Mucci, Vito Vanella, Lucia Festino, Bruno Daniele, Paolo Antonio Ascierto, Margaret Ottaviano, On Behalf Of Scito Youth.
      Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.
    Keywords:  DNA methylation; chromatin remodeling; epigenetic drugs; epigenetics; melanoma; non-coding RNA; therapeutic resistance
    DOI:  https://doi.org/10.3390/cells10082048
  34. Intern Med. 2021 Aug 24.
    Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer.
    Reiko Matsuzawa, Masahiro Morise, Ichidai Tanaka, Shunsaku Hayai, Yutaro Tamiya, Junji Koyama, Tetsunari Hase, Keiko Wakahara, Kim Deoksu, Yoshie Shimoyama, Naozumi Hashimoto.
      Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.
    Keywords:  Amelanotic melanoma; BRAF V600E mutation; Differential diagnosis; Lung tumor; immunohistochemical staining
    DOI:  https://doi.org/10.2169/internalmedicine.6657-20
  35. Cancers (Basel). 2021 Aug 18. pii: 4146. [Epub ahead of print]13(16):
    Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma.
    Zahra Souri, Aart G Jochemsen, Annemijn P A Wierenga, Wilma G M Kroes, Rob M Verdijk, Pieter A van der Velden, Gregorius P M Luyten, Martine J Jager.
      In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFNγ (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFNγ induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells.
    Keywords:  BAP1; chromosome 3; histone deacetylase; inflammation; metastasis; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13164146
  36. Nat Commun. 2021 Aug 27. 12(1): 5155
    The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma.
    Lars Ny, Henrik Jespersen, Joakim Karlsson, Samuel Alsén, Stefan Filges, Charlotta All-Eriksson, Bengt Andersson, Ana Carneiro, Hildur Helgadottir, Max Levin, Ingrid Ljuslinder, Roger Olofsson Bagge, Vasu R Sah, Ulrika Stierner, Anders Ståhlberg, Gustav Ullenhag, Lisa M Nilsson, Jonas A Nilsson.
      Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016-002114-50.
    DOI:  https://doi.org/10.1038/s41467-021-25332-w
  37. Antioxidants (Basel). 2021 Jul 27. pii: 1202. [Epub ahead of print]10(8):
    Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis.
    Hyun Kyung Lee, Jae Won Ha, Yun Jeong Hwang, Yong Chool Boo.
      The purpose of this study is to identify amino acid derivatives with potent anti-eumelanogenic activity. First, we compared the effects of twenty different amidated amino acids on tyrosinase (TYR)-mediated dopachrome formation in vitro and melanin content in dark-pigmented human melanoma MNT-1 cells. The results showed that only L-cysteinamide inhibited TYR-mediated dopachrome formation in vitro and reduced the melanin content of cells. Next, the antimelanogenic effect of L-cysteinamide was compared to those of other thiol compounds (L-cysteine, N-acetyl L-cysteine, glutathione, L-cysteine ethyl ester, N-acetyl L-cysteinamide, and cysteamine) and positive controls with known antimelanogenic effects (kojic acid and β-arbutin). The results showed the unique properties of L-cysteinamide, which effectively reduces melanin content without causing cytotoxicity. L-Cysteinamide did not affect the mRNA and protein levels of TYR, tyrosinase-related protein 1, and dopachrome tautomerase in MNT-1 cells. L-Cysteinamide exhibited similar properties in normal human epidermal melanocytes (HEMs). Experiments using mushroom TYR suggest that L-cysteinamide at certain concentrations can inhibit eumelanin synthesis through a dual mechanism by inhibiting TYR-catalyzed dopaquinone synthesis and by diverting the synthesized dopaquinone to the formation of DOPA-cysteinamide conjugates rather than dopachrome. Finally, L-cysteinamide was shown to increase pheomelanin content while decreasing eumelanin and total melanin contents in MNT-1 cells. This study suggests that L-cysteinamide has an optimal structure that can effectively and safely inhibit eumelanin synthesis in MNT-1 cells and HEMs, and will be useful in controlling skin hyperpigmentation.
    Keywords:  L-cysteinamide; MNT-1 melanoma; eumelanin; melanin; normal human melanocytes; tyrosinase; viability
    DOI:  https://doi.org/10.3390/antiox10081202
  38. Cancer Treat Res Commun. 2021 Aug 19. pii: S2468-2942(21)00144-1. [Epub ahead of print]29 100447
    Gene expression profiling in melanoma: A view from the clinic.
    S M Bollard, C Casalou, S M Potter.
      The treatment of Melanoma, one of the most aggressive human malignancies, has been revolutionised by the advent of novel targeted and immuno-therapies. However, methods utilised to detect early presentations, and to stratify risk for patients diagnosed with invasive melanoma in the clinical setting are lagging. The primary prognostic indicator is restricted to Breslow Thickness, or depth the tumour invades into the dermis. Gene Expression Profiling (GEP), the analysis of molecular gene signatures of an individual tumour, has been implemented with great success in other malignancies, such as breast and prostate cancer. In the setting of melanoma, commercial GEP panels are becoming available, offering patients a personalised approach, though yet to enter widespread clinical use. This short perspective seeks to describe how GEP is currently employed in practice, and its current clinical impact. We also suggest the potential roles for GEP in meeting the key clinical challenges faced by clinicians in melanoma treatment, such as decisions around adjuvant therapy, sentinel lymph node biopsy (SLNB) and surgical resection , thus highlighting areas for future potential research.
    Keywords:  Gene expression; Melanoma; Personalised treatment; Skin cancer
    DOI:  https://doi.org/10.1016/j.ctarc.2021.100447
  39. Biomolecules. 2021 Aug 15. pii: 1213. [Epub ahead of print]11(8):
    Cell Adhesion Molecules in Normal Skin and Melanoma.
    Cian D'Arcy, Christina Kiel.
      Cell adhesion molecules (CAMs) of the cadherin, integrin, immunoglobulin, and selectin protein families are indispensable for the formation and maintenance of multicellular tissues, especially epithelia. In the epidermis, they are involved in cell-cell contacts and in cellular interactions with the extracellular matrix (ECM), thereby contributing to the structural integrity and barrier formation of the skin. Bulk and single cell RNA sequencing data show that >170 CAMs are expressed in the healthy human skin, with high expression levels in melanocytes, keratinocytes, endothelial, and smooth muscle cells. Alterations in expression levels of CAMs are involved in melanoma propagation, interaction with the microenvironment, and metastasis. Recent mechanistic analyses together with protein and gene expression data provide a better picture of the role of CAMs in the context of skin physiology and melanoma. Here, we review progress in the field and discuss molecular mechanisms in light of gene expression profiles, including recent single cell RNA expression information. We highlight key adhesion molecules in melanoma, which can guide the identification of pathways and strategies for novel anti-melanoma therapies.
    Keywords:  GTEx consortium; Human Protein Atlas; cadherins; integrins; melanocytes; selectins; single cell RNA sequencing; tumour microenvironment
    DOI:  https://doi.org/10.3390/biom11081213
  40. Pharmaceuticals (Basel). 2021 Jul 30. pii: 749. [Epub ahead of print]14(8):
    A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine.
    Chiara R Dart, Nabanita Mukherjee, Carol M Amato, Anabel Goulding, Morgan MacBeth, Robert Van Gulick, Kasey L Couts, James R Lambert, David A Norris, William A Robinson, Yiqun G Shellman.
      Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials.
    Keywords:  BH3 mimetic; azacitidine; melanoma
    DOI:  https://doi.org/10.3390/ph14080749
  41. J Biochem Mol Toxicol. 2021 Aug 23. e22895
    Inhibition of spindle and kinetochore associated complex subunit 3 suppresses the proliferation and invasion and induced the apoptosis of cutaneous melanoma by affecting the PI3K/Akt pathway.
    Yan Liang, Yan Zheng, Kuanhou Mou, Dan Han, Lijuan Wang, Rui Ge, Anfeng Meng.
      Spindle and kinetochore-associated complex subunit 3 (SKA3) is reportedly a key contributor to the progression of various cancers. The present work aimed to evaluate the possible role of SKA3 in cutaneous melanoma (CM). A high SKA3 level was found in CM tissues and predicted a poor prognosis. SKA3 silencing markedly repressed the proliferation, invasion, and epithelial-mesenchymal transition and induced the apoptosis of CM cells. SKA3 silencing decreased the phosphorylation of PI3K and Akt. Akt inhibition markedly reversed SKA3 overexpression-induced oncogenic effects on CM cells. SKA3 silencing significantly prohibited the formation and growth of CM-derived xenograft tumors in nude mice in vivo. Our findings demonstrated SKA3 inhibition repressed the progression of CM by downregulating the PI3K/Akt pathway. This study indicates that SKA3 has potential as an anticancer candidate for CM.
    Keywords:  Akt; PI3K; SKA3; cutaneous melanoma; oncogene
    DOI:  https://doi.org/10.1002/jbt.22895
  42. Molecules. 2021 Aug 17. pii: 4963. [Epub ahead of print]26(16):
    Novel Anti-Melanogenic Compounds, (Z)-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights.
    Heejeong Choi, Il Young Ryu, Inkyu Choi, Sultan Ullah, Hee Jin Jung, Yujin Park, Yeongmu Jeong, YeJi Hwang, Sojeong Hong, In-Soo Yoon, Hwayoung Yun, Min-Soo Kim, Jin-Wook Yoo, Yunjin Jung, Pusoon Chun, Hyung Ryong Moon.
      To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve (Z)-5-(substituted benzylidene)-4-thioxothiazolidin-2-one ((Z)-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound 2b (IC50 = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds 2b and 2f are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that 2b and 2f might potently inhibit human tyrosinase. In vitro assays of 2b and 2f were conducted using B16F10 melanoma cells. Compounds 2b and 2f significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of 2b at 10 µM and 2f at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds 2b and 2f similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.
    Keywords:  PUSTC scaffold; anti-melanogenic effect; docking simulation; tyrosinase
    DOI:  https://doi.org/10.3390/molecules26164963
  43. PLoS One. 2021 ;16(8): e0256622
    Melanocyte progenitor cells reside in human subcutaneous adipose tissue.
    Yuri Ikeda, Akino Wada, Toshio Hasegawa, Mutsumi Yokota, Masato Koike, Shigaku Ikeda.
      Based on the assumption that some progenitor cells in an organ might reside in neighboring adipose tissue, we investigated whether melanocyte progenitor cells reside in human subcutaneous adipose tissue. First, we examined the expression of human melanoma black 45 (HMB45) and microphthalmia-associated transcription factor (MITF) in undifferentiated adipose-derived stem cells (ADSCs) by immunostaining, RT-PCR, and western blotting. These two markers were detected in undifferentiated ADSCs, and their expression levels were increased in differentiated ADSCs in melanocyte-specific culture medium. Other melanocytic markers (Melan A, MATP, Mel2, Mel EM, tyrosinase, KIT, and PAX3) were also detected at variable levels in undifferentiated ADSCs, and the expression of some markers was increased during differentiation into the melanocyte lineage. We further showed that ADSCs differentiated in melanocyte-specific culture medium localized in the basal layer and expressed tyrosinase and HMB45 in a 3D epidermal culture system. Melanin deposits were also induced by ultraviolet-light-B (UVB) irradiation. These results demonstrate that melanocyte progenitor cells reside in human subcutaneous adipose tissue and that these cells might have the potential to differentiate into mature melanocytes. Melanocyte and keratinocyte progenitors residing in human subcutaneous tissue can be used for the treatment of skin diseases and skin rejuvenation in the future.
    DOI:  https://doi.org/10.1371/journal.pone.0256622
  44. Cancers (Basel). 2021 Aug 15. pii: 4110. [Epub ahead of print]13(16):
    EVI2B Is a New Prognostic Biomarker in Metastatic Melanoma with IFNgamma Associated Immune Infiltration.
    Satoru Yonekura, Kosuke Ueda.
       BACKGROUND: To assess the prognostic role and the antitumor immunological relevance of ecotropic viral integration site 2B (EVI2B) in metastatic melanoma.
    METHODS: In this study, we integrated clinical data, mRNA expression data, and the distribution and fraction of tumor infiltrating lymphocytes (TILs) using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE65904 and GSE19234).
    RESULTS: The univariate and multivariate analyses showed that higher gene expression of EVI2B was significantly associated with longer prognoses. The EVI2B-high melanoma tissue had favorable histological parameters such as a brisk global distribution pattern and clustering structure of TILs (i.e., Banfield and Raftery index) with enriched CD8+ T cells over regulatory T cells and increased cytotoxicity scores. In addition, EVI2B expression positively correlated with IFN-γ signature genes (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG, and STAT1) and other various immunomodulatory genes.
    CONCLUSION: EVI2B is a novel prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma.
    Keywords:  EVI2B; IFN-γ; biomarker; melanoma; microenvironment; tumor-infiltrating
    DOI:  https://doi.org/10.3390/cancers13164110
  45. Cancers (Basel). 2021 Aug 05. pii: 3943. [Epub ahead of print]13(16):
    CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma.
    Alba Gutiérrez-Seijo, Elena García-Martínez, Celia Barrio-Alonso, Miriam Pareja-Malagón, Alejandra Acosta-Ocampo, María Eugenia Fernández-Santos, Amaya Puig-Kröger, Verónica Parra-Blanco, Enrique Mercader, Iván Márquez-Rodas, José Antonio Avilés-Izquierdo, Rafael Samaniego, Paloma Sánchez-Mateos.
      TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. We explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; in addition, because cytokine production is a hallmark of macrophages function, we measured CCL20, TNF, and VEGFA intracellular cytokines by single-cell multiparametric confocal microscopy. The Kaplan-Meier method was used to analyze correlation with melanoma-specific disease-free survival and overall survival. No significant correlations with clinical parameters were observed for TAM density, morphology, or location. Significantly, higher contents of the intracellular cytokines CCL20, TNF, and VEGFA were quantified in TAMs infiltrating metastasizing compared to non-metastasizing skin primary melanomas (p < 0.001). To mechanistically explore cytokine up-regulation, we performed in vitro studies with melanoma-conditioned macrophages, using RNA-seq to explore involved pathways and specific inhibitors. We show that p53 and NF-κB coregulate CCL20, TNF, and VEGFA in melanoma-conditioned macrophages. These results delineate a clinically relevant pro-oncogenic cytokine profile of TAMs with prognostic significance in primary melanomas and point to the combined therapeutic targeting of NF-kB/p53 pathways to control the deviation of TAMs in melanoma.
    Keywords:  CCL20; TAM; TNF; VEGFA; biomarker; melanoma; metastasis; prognostic factor
    DOI:  https://doi.org/10.3390/cancers13163943
  46. Mol Oncol. 2021 Aug 21.
    hnRNP-A1 binds to the IRES of MELOE-1 antigen to promote its translation in stressed melanoma cells.
    Maud Charpentier, Emilie Dupré, Agnès Fortun, Floriane Briand, Mike Maillasson, Emmanuelle Com, Charles Pineau, Nathalie Labarrière, Catherine Rabu, François Lang.
      The major challenge in antigen-specific immunotherapy of cancer is to select the most relevant tumor antigens to target. To this aim, understanding their mode of expression by tumor cells is critical. We previously identified a melanoma-specific antigen, melanoma-overexpressed antigen 1 (MELOE-1) - coded for by a long non-coding RNA - whose internal ribosomal entry sequence (IRES)-dependent translation is restricted to tumor cells. This restricted expression is associated with the presence of a broad specific T cell repertoire that is involved in tumor immunosurveillance in melanoma patients. In the present work, we explored the translation control of MELOE-1 and provide evidence that heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) binds to the MELOE-1 IRES and acts as an IRES trans-activating factor (ITAF) to promote the translation of MELOE-1 in melanoma cells. In addition, we showed that endoplasmic reticulum (ER) stress induced by thapsigargin, which promotes hnRNP-A1 cytoplasmic translocation, enhances MELOE-1 translation and recognition of melanoma cells by a MELOE-1-specific T cell clone. These findings suggest that pharmacological stimulation of stress pathways may enhance the efficacy of immunotherapies targeting stress-induced tumor antigens such as MELOE-1.
    Keywords:  ER stress; IRES; ITAF; long non coding RNA; melanoma; tumor antigens
    DOI:  https://doi.org/10.1002/1878-0261.13088
  47. J Clin Med. 2021 Aug 23. pii: 3760. [Epub ahead of print]10(16):
    Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management.
    Lamberto Zocchi, Alberto Lontano, Martina Merli, Emi Dika, Eduardo Nagore, Pietro Quaglino, Susana Puig, Simone Ribero.
      A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.
    Keywords:  BAP1; CDK4; CDKN2A; MC1R; MITF; POT1; dermoscopy; familial melanoma; genetic; multiple melanoma
    DOI:  https://doi.org/10.3390/jcm10163760
  48. Cancers (Basel). 2021 Aug 15. pii: 4111. [Epub ahead of print]13(16):
    Molecular Changes Induced in Melanoma by Cell Culturing in 3D Alginate Hydrogels.
    Melanie Kappelmann-Fenzl, Sonja K Schmidt, Stefan Fischer, Rafael Schmid, Lisa Lämmerhirt, Lena Fischer, Stefan Schrüfer, Ingo Thievessen, Dirk W Schubert, Alexander Matthies, Rainer Detsch, Aldo R Boccaccini, Andreas Arkudas, Annika Kengelbach-Weigand, Anja K Bosserhoff.
      Alginate hydrogels have been used as a biomaterial for 3D culturing for several years. Here, gene expression patterns in melanoma cells cultivated in 3D alginate are compared to 2D cultures. It is well-known that 2D cell culture is not resembling the complex in vivo situation well. However, the use of very intricate 3D models does not allow performing high-throughput screening and analysis is highly complex. 3D cell culture strategies in hydrogels will better mimic the in vivo situation while they maintain feasibility for large-scale analysis. As alginate is an easy-to-use material and due to its favorable properties, it is commonly applied as a bioink component in the growing field of cell encapsulation and biofabrication. Yet, only a little information about the transcriptome in 3D cultures in hydrogels like alginate is available. In this study, changes in the transcriptome based on RNA-Seq data by cultivating melanoma cells in 3D alginate are analyzed and reveal marked changes compared to cells cultured on usual 2D tissue culture plastic. Deregulated genes represent valuable cues to signaling pathways and molecules affected by the culture method. Using this as a model system for tumor cell plasticity and heterogeneity, EGR1 is determined to play an important role in melanoma progression.
    Keywords:  3D cultivation; EGR1; biomaterials; melanoma; whole transcriptome
    DOI:  https://doi.org/10.3390/cancers13164111
  49. Diagnostics (Basel). 2021 Jul 26. pii: 1341. [Epub ahead of print]11(8):
    Unraveling the Wide Spectrum of Melanoma Biomarkers.
    Antonios Revythis, Sidrah Shah, Mikolaj Kutka, Michele Moschetta, Mehmet Akif Ozturk, George Pappas-Gogos, Evangelia Ioannidou, Matin Sheriff, Elie Rassy, Stergios Boussios.
      The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow's original report on "melanoma and prognostic values of thickness", providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.
    Keywords:  biomarkers; genetic mutations; melanoma; molecular pathology; prognosis
    DOI:  https://doi.org/10.3390/diagnostics11081341
  50. Vet Sci. 2021 Aug 01. pii: 154. [Epub ahead of print]8(8):
    Metastatic Cutaneous Melanoma in a White African Lioness (Panthera leo).
    Louise van der Weyden, Peter Caldwell, Liesl van Rooyen, Emily P Mitchell, Nicolize O'Dell.
      Malignant melanomas tend to be locally destructive, aggressive tumours commonly associated with recurrence and/or metastasis. In this report, a 13-year-old captive white African lioness (Panthera leo), with a recent history of intermittent bouts of lethargy and inappetence, presented with a distended abdomen (due to ascites) and a small, round crusty lesion on the ear. An abdominal ultrasound showed the presence of masses on the liver and an exploratory laparotomy revealed multiple pale lesions on the liver and omentum. Histopathology revealed sheets of pleomorphic neoplastic cells compressing the non-neoplastic liver tissue. Similar neoplastic cells had multifocally expanded and effaced omentum adipose tissue, as well as formed a well-circumscribed mass in the ear sample, extending from close to the epidermis to the lateral and deep margins of the section. All three tissue samples had a high mitotic index (15 per 10 HPF), and critically, in the ear sample, there were rafts of neoplastic cells in the lymphatics, indicating lymphovascular invasion. Immunohistochemistry for the melanoma marker, PNL-2, showed strong positivity in all three tissue samples. Thus, the diagnosis was of malignant melanoma with metastasis to the liver and omentum. This is the first report of metastatic cutaneous melanoma in a lion.
    Keywords:  PNL-2; cutaneous; lion; melanoma; metastasis; skin
    DOI:  https://doi.org/10.3390/vetsci8080154
  51. Cancers (Basel). 2021 Aug 05. pii: 3948. [Epub ahead of print]13(16):
    Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect.
    Kazumasa Oya, Yoshiyuki Nakamura, Zhu Zhenjie, Ryota Tanaka, Naoko Okiyama, Yuki Ichimura, Yosuke Ishitsuka, Akimasa Saito, Noriko Kubota, Rei Watanabe, Hideaki Tahara, Manabu Fujimoto, Yasuhiro Fujisawa.
      The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.
    Keywords:  anti-PD-1 antibody; combination therapy; imiquimod; melanoma
    DOI:  https://doi.org/10.3390/cancers13163948
  52. Dermatol Pract Concept. 2021 Jul;11(Suppl 1): e2021162S
    Melanoma: Staging and Follow-Up.
    Chryssoula Papageorgiou, Zoe Apalla, Sofia-Magdalini Manoli, Konstantinos Lallas, Efstratios Vakirlis, Aimilios Lallas.
      Cancer staging is the process determining to which extent a cancer has spread and where it is located in the body. A thorough staging is of utmost importance, not only because it provides the most accurate prognostic estimation, but also because several crucial decisions, such as the treatment choice and the follow-up strategy, vary according to the tumor's stage. The current staging system for melanoma is based on the 8th edition of TNM classification issued by the American Joint Committee on Cancer (AJCC) in 2017. It includes a clinical and a pathological staging, both consisting of 5 stages (0-IV). The stage of a melanoma is determined by several factors, among which the Breslow thickness, the pathological presence or absence of ulceration in the primary tumor, the presence and the number of tumor-involved regional lymph nodes, the presence or absence of in-transit, satellite and/or microsatellite metastases, and the presence of distant metastases. Following melanoma diagnosis, an accurate medical workup, in line with the stage and the physical examination, should be performed. A continuous patient monitoring is fundamental to detect a potential relapse or a second primary melanoma and should be lifelong. However, there is still no universally adopted follow-up strategy program and different follow-up schemes have been suggested. Future prospective studies are needed to evaluate different follow-up protocols according to the adopted therapy, as novel recent therapies (targeted and immunotherapies) are being increasingly used. Key MessagesProper staging is of utmost importance because it provides accurate prognostic estimation. Several crucial decisions, such as the treatment choice and the follow up strategy, are based on the tumor stage.Physical examination during staging procedure and follow-up visits are important to avoid unnecessary imaging and laboratory tests that could increase the patients' anxiety. A personalized approach taking into consideration the patient's risk factors, is strongly recommended.Melanoma patients should be kept under surveillance lifelong due to an increased risk of developing a second primary melanoma and the risk of recurrence. Higher intensity follow-up strategies during the first 5 years are recommended due to higher rates of regional or distant relapse.
    Keywords:  Melanoma; follow-up; staging
    DOI:  https://doi.org/10.5826/dpc.11S1a162S
  53. Genes (Basel). 2021 Jul 25. pii: 1130. [Epub ahead of print]12(8):
    GNAI2 Promotes Proliferation and Decreases Apoptosis in Rabbit Melanocytes.
    Shuaishuai Hu, Yingying Dai, Shaocheng Bai, Bohao Zhao, Xinsheng Wu, Yang Chen.
      GNAI2 (G protein subunit alpha i2) is a signaling modulator or transducer, involved in several transmembrane signaling systems, that plays a vital role in the melanogenesis signaling pathway. However, whether GNAI2 regulates cell proliferation and apoptosis in rabbit melanocytes is not known. We found that GNAI2 was differentially expressed in rabbits with different coat colors using qRT-PCR and Wes assays. Furthermore, it was observed that the rabbits with black skin had the highest GNAI2 levels, and those with white skin had the lowest expression. The coding sequence of GNAI2 was successfully cloned and inserted into pcDNA3.1 and pcDNA3.1-Myc vectors. It was observed that the GNAI2 protein was mainly localized in the cytoplasm using the indirect immunofluorescence staining assay. Overexpression of GNAI2 significantly increased melanin content, promoted melanocyte proliferation, and inhibited melanocyte apoptosis. On the contrary, the knockdown of GNAI2 using siRNA had the opposite effect. In addition, GNAI2 significantly increased the mRNA expression levels of the melanin-related genes TYR, GPNMB, PMEL, and DCT in rabbit melanocytes. The results suggested that GNAI2 regulated melanocyte development by promoting melanocyte proliferation and inhibiting apoptosis.
    Keywords:  GNAI2; apoptosis; melanocyte; proliferation
    DOI:  https://doi.org/10.3390/genes12081130
  54. Biomedicines. 2021 Jul 26. pii: 896. [Epub ahead of print]9(8):
    TGF-β Increases MFGE8 Production in Myeloid-Derived Suppressor Cells to Promote B16F10 Melanoma Metastasis.
    Heejin Lim, Taewoo Yang, Wongeun Lee, Sung-Gyoo Park.
      There is growing evidence that myeloid-derived suppressor cells (MDSCs) are directly involved in all stages leading to metastasis. Many mechanisms for this effect have been proposed, but mechanisms of coregulation between tumor cells and MDSCs remain poorly understood. In this study, we demonstrate that MDSCs are a source of milk fat globule-epidermal growth factor (EGF) factor 8 (MFGE8), which is known to be involved in tumor metastasis. Interestingly, TGF-β, an abundant cytokine in the tumor microenvironment (TME), increased MFGE8 production by MDSCs. In addition, co-culturing MDSCs with B16F10 melanoma cells increased B16F10 cell migration, while MFGE8 neutralization decreased their migration. Taken together, these findings suggest that MFGE8 is an important effector molecule through which MDSCs promote tumor metastasis, and the TME positively regulates MFGE8 production by MDSCs through TGF-β.
    Keywords:  MFGE8; TGF-β; metastasis; myeloid-derived suppressor cells; tumor
    DOI:  https://doi.org/10.3390/biomedicines9080896
  55. J Invest Dermatol. 2021 Aug 18. pii: S0022-202X(21)01689-4. [Epub ahead of print]
    Co-expression of MTH1 and PMS2 is associated with advanced disease and disease progression after therapy in melanoma.
    Ishani Das, Rainer Tuominen, Thomas Helleday, Johan Hansson, Ulrika Warpman Berglund, Suzanne Egyházi Brage.
      
    DOI:  https://doi.org/10.1016/j.jid.2021.07.166
  56. Pathology. 2021 Aug 19. pii: S0031-3025(21)00422-0. [Epub ahead of print]
    Dedifferentiated melanoma with MDM2 gene amplification mimicking dedifferentiated liposarcoma.
    Samer Yousef, Christopher Joy, Shanta Velaiutham, Fiona M Maclean, James Harraway, Anthony J Gill, Ana Cristina Vargas.
      
    DOI:  https://doi.org/10.1016/j.pathol.2021.05.096
  57. Indian J Dermatol Venereol Leprol. 2021 Sep-Oct;87(5):pii: 10.25259/IJDVL_498_20. [Epub ahead of print]87(5): 723-725
    Validity and feasibility of the self-assessment vitiligo extent score among Egyptian patients.
    Marwa Abdallah, Ahmed Nassar, Miriam Samir, Abd-Elrahman Reda, Aya Hassan, Moahmed F Allam, Rania Mahmoud Elhusseiny.
      
    DOI:  https://doi.org/10.25259/IJDVL_498_20
  58. Cancers (Basel). 2021 Aug 04. pii: 3924. [Epub ahead of print]13(16):
    The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent-DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors.
    Alina Drzyzga, Tomasz Cichoń, Justyna Czapla, Magdalena Jarosz-Biej, Ewelina Pilny, Sybilla Matuszczak, Piotr Wojcieszek, Zbigniew Urbaś, Ryszard Smolarczyk.
      Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells on the edge of the tumor that are responsible for tumor regrowth. The aim of the study was to combine DMXAA with radiotherapy (brachytherapy) and find the appropriate administration sequence to obtain the maximum synergistic therapeutic effect. We show that the combination in which tumors were irradiated prior to VDAs administration is more effective in murine melanoma growth inhibition than in either of the agents individually or in reverse combination. For the first time, the significance of immune cells' activation in such a combination is demonstrated. The inhibition of tumor growth is linked to the reduction of tumor blood vessels, the increased infiltration of CD8+ cytotoxic T lymphocytes and NK cells and the polarization of macrophages to the cytotoxic M1 phenotype. The reverse combination of therapeutic agents showed no therapeutic effect and even abolished the effect of DMXAA. The combination of brachytherapy and vascular disrupting agent effectively inhibits the growth of melanoma tumors but requires careful planning of the sequence of administration of the agents.
    Keywords:  brachytherapy; combined anti-cancer therapy; immunotherapy; radiotherapy; vascular disrupting agents
    DOI:  https://doi.org/10.3390/cancers13163924
  59. Front Genet. 2021 ;12 707228
    Phylogenetic Analysis of Core Melanin Synthesis Genes Provides Novel Insights Into the Molecular Basis of Albinism in Fish.
    Chao Bian, Ruihan Li, Zhengyong Wen, Wei Ge, Qiong Shi.
      Melanin is the most prevalent pigment in animals. Its synthesis involves a series of functional genes. Particularly, teleosts have more copies of these genes related to the melanin synthesis than tetrapods. Despite the increasing number of available vertebrate genomes, a few systematically genomic studies were reported to identify and compare these core genes for the melanin synthesis. Here, we performed a comparative genomic analysis on several core genes, including tyrosinase genes (tyr, tyrp1, and tyrp2), premelanosome protein (pmel), microphthalmia-associated transcription factor (mitf), and solute carrier family 24 member 5 (slc24a5), based on 90 representative vertebrate genomes. Gene number and mutation identification suggest that loss-of-function mutations in these core genes may interact to generate an albinism phenotype. We found nonsense mutations in tyrp1a and pmelb of an albino golden-line barbel fish, in pmelb of an albino deep-sea snailfish (Pseudoliparis swirei), in slc24a5 of cave-restricted Mexican tetra (Astyanax mexicanus, cavefish population), and in mitf of a transparent icefish (Protosalanx hyalocranius). Convergent evolution may explain this phenomenon since nonsense mutations in these core genes for melanin synthesis have been identified across diverse albino fishes. These newly identified nonsense mutations and gene loss will provide molecular guidance for ornamental fish breeding, further enhancing our in-depth understanding of human skin coloration.
    Keywords:  albinism phenotype; core genes for melanin synthesis; melanin synthesis pathway; nonsense mutation; phylogenetic analysis
    DOI:  https://doi.org/10.3389/fgene.2021.707228
  60. Front Med (Lausanne). 2021 ;8 681668
    A Clinicopathological Analysis of Melanocytic Nevi: A Retrospective Series.
    Panpan Liu, Juan Su, Xuanwei Zheng, Mingliang Chen, Xiang Chen, Jie Li, Cong Peng, Yehong Kuang, Wu Zhu.
      Purpose: Melanocytic nevi are common cutaneous lesions. This study aimed to demonstrate the concordance and discordance between clinical and histopathological diagnoses of melanocytic nevi and the importance of histological evaluation in differentiating malignant lesions from diseases with similar clinical manifestations. Patients and Methods: We studied 4,561 consecutive patients with a clinical diagnosis of melanocytic nevi from 2014 to 2019. We compared the clinical diagnosis with the histopathological diagnosis to establish a histopathological concordance rate and then investigated the effects of clinical characteristics and the reasons for removal on misclassification. Results: Among 4,561 patients who were clinically diagnosed with melanocytic nevi, the overall histopathological concordance rate was 82.11% (3,745 of 4,561 patients), while the histopathological discordance rate was 17.89% (816 of 4,561 patients). The histopathological concordance included 90.25% common acquired melanocytic nevi (3,380 of 3,745 patients) and 9.75% other benign melanocytic neoplasms (365 of 3,745 patients). The most common diagnostic change was to seborrheic keratosis (n = 470, 10.30%), followed by basal cell carcinoma (n = 64, 1.40%), vascular tumor (n = 53, 1.16%), fibroma (n = 43, 0.94%), epidermoid cyst (n = 34, 0.75%), wart (n = 30, 0.66%), melanoma (n = 24, 0.53%), Bowen's disease (n = 16, 0.35%), squamous cell carcinoma (n = 4, 0.09%), keratoacanthoma (n = 2, 0.04%), and other neoplasms (n = 76, 1.67%). Male sex, old age, location of the lesion, and the reasons for removal have a potential effect on misclassification. The percentages of misclassified lesions on the trunk and limbs and the perineum and buttocks were higher than those in lesions without a change in diagnosis. Importantly, locations of lesions on the head and neck were significantly related to a change in diagnosis to non-melanoma skin cancer, while locations on the hands and feet were significantly related to a change in diagnosis to melanoma. In addition to a typical clinical features, removal due to lesion changes or repeated stimulation was significantly associated with a change in diagnosis to melanoma. Conclusions: Our study emphasizes the clinical differential diagnosis of melanocytic nevi, especially the possibility of malignant tumors. The occurrence of clinical features associated with clinicopathological discordance should raise the clinical suspect and be carefully differentiated from malignant tumors.
    Keywords:  diagnosis; melanocytic diseases; melanocytic nevi; melanoma; misclassification
    DOI:  https://doi.org/10.3389/fmed.2021.681668
  61. Pharmaceutics. 2021 Jul 27. pii: 1155. [Epub ahead of print]13(8):
    Morus alba Root Extract Induces the Anagen Phase in the Human Hair Follicle Dermal Papilla Cells.
    Jiyu Hyun, Jisoo Im, Sung-Won Kim, Han Young Kim, Inwoo Seo, Suk Ho Bhang.
      Restoring hair follicles by inducing the anagen phase is a promising approach to prevent hair loss. Hair follicle dermal papilla cells (HFDPCs) play a major role in hair growth via the telogen-to-anagen transition. The therapeutic effect of Morus alba activates β-catenin in HFDPCs, thereby inducing the anagen phase. The HFDPCs were treated with M. alba root extract (MARE) to promote hair growth. It contains chlorogenic acid and umbelliferone and is not cytotoxic to HFDPCs at a concentration of 20%. It was demonstrated that a small amount of MARE enhances growth factor secretion (related to the telogen-to-anagen transition). Activation of β-catenin was observed in MARE-treated HFDPCs, which is crucial for inducing the anagen phase. The effect of conditioned medium derived from MARE-treated HFDPCs on keratinocytes and endothelial cells was also investigated. The findings of this study demonstrate the potency of MARE in eliciting the telogen-to-anagen transition.
    Keywords:  Morus alba; anagen-inducing; growth factor secretion; hair follicle dermal papilla cells; herbal extract
    DOI:  https://doi.org/10.3390/pharmaceutics13081155
  62. Cell Res. 2021 Aug 27.
    Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor.
    Shanshan Ma, Yan Chen, Antao Dai, Wanchao Yin, Jia Guo, Dehua Yang, Fulai Zhou, Yi Jiang, Ming-Wei Wang, H Eric Xu.
      Melanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R-MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gβ subunit were discovered from these structures. Together, our results elucidate a conserved mechanism of calcium-mediated ligand recognition, a specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.
    DOI:  https://doi.org/10.1038/s41422-021-00557-y
  63. Cancers (Basel). 2021 Aug 07. pii: 3993. [Epub ahead of print]13(16):
    PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ-DNMT1 Interactions in the Genome.
    Amit Sharma, Fabian Tobar-Tosse, Tikam Chand Dakal, Hongde Liu, Arijit Biswas, Athira Menon, Anoosha Paruchuri, Panagiotis Katsonis, Olivier Lichtarge, M Michael Gromiha, Michael Ludwig, Ingo G H Schmidt-Wolf, Frank G Holz, Karin U Loeffler, Martina C Herwig-Carl.
       BACKGROUND: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined.
    METHODS: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA).
    RESULTS: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ-DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein-protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM.
    CONCLUSIONS: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.
    Keywords:  Alu repeats; DNMT1; PPARγ; cancer; evolutionary action score; repetitive sequences; uveal melanoma
    DOI:  https://doi.org/10.3390/cancers13163993
  64. Int J Mol Sci. 2021 Aug 10. pii: 8596. [Epub ahead of print]22(16):
    Cathepsin L, a Target of Hypoxia-Inducible Factor-1-α, Is Involved in Melanosome Degradation in Melanocytes.
    Ji Young Kim, Eun Jung Lee, Yuri Ahn, Sujin Park, Yu Jeong Bae, Tae Gyun Kim, Sang Ho Oh.
      Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a lysosomal protease that degrades cellular proteins via the endolysosomal pathway. In this study, we attempted to determine if CTSL is a hypoxia responsive target gene of HIF-1α, and decipher its role in melanocytes in association with the autophagic pathway. The results of our luciferase reporter assay showed that the expression of CTSL is transcriptionally activated through the binding of HIF1-α at its promoter. Under autophagy-inducing starvation conditions, HIF-1α and CTSL expression is highly upregulated in melan-a cells. The mature form of CTSL is closely involved in melanosome degradation through lysosomal activity upon autophagosome-lysosome fusion. The inhibition of conversion of pro-CTSL to mature CTSL leads to the accumulation of gp100 and tyrosinase in addition to microtubule-associated protein 1 light chain 3 (LC3) II, due to decreased lysosomal activity in the autophagic pathway. In conclusion, we have identified that CTSL, a novel target of HIF-1α, participates in melanosome degradation in melanocytes through lysosomal activity during autophagosome-lysosome fusion.
    Keywords:  Cathepsin L; autophagy; hypoxia-inducible factor-1-alpha; melanosome
    DOI:  https://doi.org/10.3390/ijms22168596
  65. Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2103020118. [Epub ahead of print]118(35):
    Catabolism of lysosome-related organelles in color-changing spiders supports intracellular turnover of pigments.
    Florent Figon, Ilse Hurbain, Xavier Heiligenstein, Sylvain Trépout, Arnaud Lanoue, Kadda Medjoubi, Andrea Somogyi, Cédric Delevoye, Graça Raposo, Jérôme Casas.
      Pigment organelles of vertebrates belong to the lysosome-related organelle (LRO) family, of which melanin-producing melanosomes are the prototypes. While their anabolism has been extensively unraveled through the study of melanosomes in skin melanocytes, their catabolism remains poorly known. Here, we tap into the unique ability of crab spiders to reversibly change body coloration to examine the catabolism of their pigment organelles. By combining ultrastructural and metal analyses on high-pressure frozen integuments, we first assess whether pigment organelles of crab spiders belong to the LRO family and second, how their catabolism is intracellularly processed. Using scanning transmission electron microscopy, electron tomography, and nanoscale Synchrotron-based scanning X-ray fluorescence, we show that pigment organelles possess ultrastructural and chemical hallmarks of LROs, including intraluminal vesicles and metal deposits, similar to melanosomes. Monitoring ultrastructural changes during bleaching suggests that the catabolism of pigment organelles involves the degradation and removal of their intraluminal content, possibly through lysosomal mechanisms. In contrast to skin melanosomes, anabolism and catabolism of pigments proceed within the same cell without requiring either cell death or secretion/phagocytosis. Our work hence provides support for the hypothesis that the endolysosomal system is fully functionalized for within-cell turnover of pigments, leading to functional maintenance under adverse conditions and phenotypic plasticity. First formulated for eye melanosomes in the context of human vision, the hypothesis of intracellular turnover of pigments gets unprecedented strong support from pigment organelles of spiders.
    Keywords:  endosome; melanosome; mimicry; ommochrome; pigment granule
    DOI:  https://doi.org/10.1073/pnas.2103020118
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