bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2021‒01‒10
27 papers selected by
Laura Mannarino
Mario Negri Institute

  1. Cancers (Basel). 2021 Jan 03. pii: E127. [Epub ahead of print]13(1):
      The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management.
    Keywords:  metabolism; miR; tumor microenvironment
  2. Anticancer Res. 2021 Jan;41(1): 359-368
      BACKGROUND/AIM: Surgical resection for soft tissue sarcomas (STSs) is the gold standard for a curative oncologic therapy in combination with neoadjuvant or adjuvant radiation therapy (NRT/ART). The aim of this study was to determine prognostic factors influencing the survival of patients with STS undergoing NRT or ART considering various parameters in a retrospective, single-centre analysis over 15 years.PATIENTS AND METHODS: We included 119 patients (male 59) and the median follow-up period was 69 months (4-197). The patients received NRT (n=64) or ART (n=55). We recorded the histopathologic subtype of STS, tumour grade, localization, tumour margins, complications, survival, local recurrence, and metastases. Survival analysis was performed using the Kaplan-Meier method.
    RESULTS: The overall survival rate was 68.9% at 5 years. The localization (epifascial/subfascial), resection margin and type of radiation therapy (NRT/ART) had no significant impact on survival. Tumour grade, tumour size, local recurrence and metastases were significantly correlated with patient survival (p<0.05). Local recurrence was significantly higher in patients with ART (p=0.044).
    CONCLUSION: Tumour grade and tumour size were independently associated with disease-specific survival, and patients with local recurrence and metastases had lower survival rates.
    Keywords:  Soft tissue sarcoma; prognostic factors; radiation therapy; surgery
  3. Curr Cancer Drug Targets. 2021 Jan 06.
      Long non-coding RNAs (LncRNAs) epitomize a class of non-coding regulatory RNAs with more than 200 nucleotides long and situated in the nucleus or cytoplasm and rarely encode proteins. Accruing evidence signposts that lncRNAs act as molecular switches in different cellular activities like differentiation, apoptosis as well as reprogramming of cellular states by modifying gene expression patterns. The revelation of immense numbers of lncRNA with their widespread variety of expression patterns in different kinds of malignancy, tumor explicitness and their steadiness in circulating body fluids deliver an innovative groundwork for emerging diagnosis and treatments for cancer. Mechanisms associating lncRNAs in carcinogenesis are conquered by deregulation of cellular signaling pathways and altered epitranscriptome along with their expression. Specified these attributes, it becomes clear that the improvement of new tools to identify lncRNAs with higher affectability will be fundamental to allow the identification of expression pattern of lncRNAs in various kinds of malignant growth and may likewise be utilized to envisage cancer prognosis in addition to patients outcome. Improvement of RNA targeting based therapeutics delivering incredible prospects to modulate lncRNAs for anti-cancer initiatives. Henceforth, lncRNAs can be used exclusively as possible cancer biomarkers for early diagnosis and anticipation of malignancy as well as metastasis. In addition to basic curative targets and along these, lncRNAs holds resilient assurance towards the revelation of innovative diagnostics and therapeutics for malignant growth with interface of epitranscriptomics information. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis, regulation and lncRNA-associated epigenetics of cancer along with targeting lncRNAs with potential approaches for impending diagnosis and therapeutic intervention in malignancies.
    Keywords:  LncRNA; epigenetic; gene expression; innovative diagnostics.; malignant growth; metastasis
  4. Biomark Res. 2021 Jan 06. 9(1): 1
      Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.
    Keywords:  Fatty acid oxidation; Fatty acid synthesis; Glycolysis; Macrophages; Metabolism
  5. Bratisl Lek Listy. 2021 ;122(1): 71-77
      OBJECTIVES: We aimed to examine the performance of stem cell markers and epithelial-mesenchymal transition (EMT) process in miR-145 transfected EWS cells (TC71, TC106).METHODS: EWS cells were utilized for functional analysis of mir-145. Proliferation, migration, invasion and soft agar colony assay were performed to observe the alterations in migration behavior of transfected cells. Caspase assay was used to investigate the underlying reasons of proliferative inhibition in cells in whichmiR-145 is overexpressed. QRT-PCR was used to determine the role of miR-145 in EMT transcription markers and mir-145 targeted genes, KLF4, SOX2 and OCT4 expression levels.
    RESULTS: The miR-145 expression has been shown to be down-regulated in EWS. The miR-145 overexpression caused inhibition of proliferation and reduced migration in EWS cells through induction of apoptosis. Mir-145 suppresses EMT capacity and SOX2, KLF4 and OCT4 expression levels.
    CONCLUSION: This is the first time in the literature we have shown deregulation of miR-145 inhibits EMT process by targeting stem cell properties leading to the inhibition of tumor growth and metastasis in TC71 and TC106 cells. Based on these results, we propose that miR-145, as an important regulator of SOX2, KLF4 and OCT4 carries crucial roles in EWS tumorigenesis and EMT (Tab. 1, Fig. 4, Ref. 26).
    Keywords:  Ewing sarcoma; mir-145 stem cell markers.
  6. Diagn Pathol. 2021 Jan 09. 16(1): 2
      BACKGROUND: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited.METHODS: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test.
    RESULTS: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001).
    CONCLUSIONS: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.
    Keywords:  IL13Rα1; IL4Rα; Prognosis; Sarcoma; Soft tissue
  7. Neoplasia. 2021 Jan 05. pii: S1476-5586(20)30190-1. [Epub ahead of print]23(2): 234-245
      Tumor cells often switch from mitochondrial oxidative metabolism to glycolytic metabolism even under aerobic conditions. Tumor cell glycolysis is accompanied by several nonenzymatic activities among which induction of drug resistance has important therapeutic implications. In this article, we review the main aspects of glycolysis-induced drug resistance. We discuss the classes of antitumor drugs that are affected and the components of the glycolytic pathway (transporters, enzymes, metabolites) that are involved in the induction of drug resistance. Glycolysis-associated drug resistance occurs in response to stimuli, either cell-autonomous (e.g., oncoproteins) or deriving from the tumor microenvironment (e.g., hypoxia or pseudohypoxia, mechanical cues, etc.). Several mechanisms mediate the induction of drug resistance in response to glycolytic metabolism: inhibition of apoptosis, induction of epithelial-mesenchymal transition, induction of autophagy, inhibition of drug influx and increase of drug efflux. We suggest that drug resistance in response to glycolysis comes into play in presence of qualitative (e.g., expression of embryonic enzyme isoforms, post-translational enzyme modifications) or quantitative (e.g., overexpression of enzymes or overproduction of metabolites) alterations of glycolytic metabolism. We also discern similarities between changes occurring in tumor cells in response to stimuli inducing glycolysis-associated drug resistance and those occurring in cells of the innate immune system in response to danger signals and that have been referred to as danger-associated metabolic modifications. Eventually, we briefly address that also mitochondrial oxidative metabolism may induce drug resistance and discuss the therapeutic implications deriving from the fact that the main energy-generating metabolic pathways may be both at the origin of antitumor drug resistance.
    Keywords:  Apoptosis; Danger; Drug resistance; EMT; Glycolysis; Tumors
  8. Mol Biol Rep. 2021 Jan 05.
      Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.
    Keywords:  Alternative Splicing; Cancer therapy; Chemoresistance; EMT/metastasis; FGFR/CD44; Splicing Factors
  9. Eur J Cancer. 2021 Jan 05. pii: S0959-8049(20)31322-8. [Epub ahead of print]144 360-367
      BACKGROUND: Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound with single-agent activity in soft tissue sarcoma (STS). The study's aim was to determine the safety and efficacy of selinexor in combination with doxorubicin in patients with locally advanced/metastatic STS.METHODS: This phase 1b study used a mTPI design. Patients received selinexor at either 60 or 80 mg weekly PO plus doxorubicin (75 mg/m2 IV q21 days). Patients with clinical benefit (defined as ≥stable disease via RECIST 1.1) after six cycles of combination treatment received maintenance selinexor until disease progression or unacceptable toxicity. Disease assessments were conducted every two cycles. Pharmacokinetic data were collected on the first three patients per dose level.
    RESULTS: Twenty-five patients were enrolled (20 female, ECOG 0/1: 13/12, median age 57 years [range 21-74]). Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumour (n = 3) and other sarcomas (n = 16). Three (12%) and 22 (88%) patients were treated at 60 mg and 80 mg of selinexor, respectively. The most common ≥G3 drug-related adverse events (AEs) were haematological, including neutropenia (56%), febrile neutropenia (28%) and anaemia (24%). There were four dose-limiting toxicities (febrile neutropenia (x2), vomiting, fatigue) all at the 80 mg dose level. There was one death secondary to heart failure. Of the 24 evaluable patients, 5 (21%) had a partial response and 15 (63%) had SD as best response. The estimated median progression-free survival (PFS) and overall survival (OS) were 5.5 (95% CI:4.1-5.7) and 10.5 (95% CI:7.5-14) months.
    CONCLUSION: In a heterogeneous group of patients with locally advanced/metastatic STS, the combination of selinexor and doxorubicin fulfilled the prespecified boundary for tolerability.
    Keywords:  Doxorubicin; Small molecule; Soft tissue sarcoma; XPO-1
  10. Oncogene. 2021 Jan 07.
      Ewing sarcoma (ES) is the second most common bone tumor in children and young adults. Unfortunately, there have been minimal recent advancements in improving patient outcomes, especially in metastatic and recurrent diseases. In this study, we investigated the biological role of p21-activated kinases (PAKs) in ES, and the ability to therapeutically target them in high-risk disease. Via informatics analysis, we established the inverse association of PAK1 and PAK4 expression with clinical stage and outcome in ES patients. Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In vitro studies in several ES cell lines indicated that diminishing PAK1 and PAK4 expression reduces tumor cell viability, migratory, and invasive properties. In vivo studies using PAK4 inhibitors, KPT-9274 and PF-3758309 demonstrated significant inhibition of primary and metastatic tumor formation, while transcriptomic analysis of PAK4-inhibitor-treated tumors identified concomitant suppression of Notch, β-catenin, and hypoxia-mediated signatures. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-ɣ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future.
  11. Anticancer Res. 2021 Jan;41(1): 527-532
      BACKGROUND: Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified.PATIENTS AND METHODS: This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival.
    RESULTS: L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR <3.0 (HR=9.96, 95% CI=1.28-77.7; p=0.028) were independent factors predictive of durable clinical benefit. In addition, pre-treatment NLR <3.0 (HR=0.34, 95% CI=0.16-0.74; p=0.0059) and male sex (HR=0.23, 95% CI=0.10-0.52; p<0.001) were independent factors predictive of better progression-free survival.
    CONCLUSION: This retrospective study found that baseline NLR predicts the efficacy of eribulin for STS.
    Keywords:  NLR; Neutrophil-to-lymphocyte ratio; STS; eribulin; soft-tissue sarcoma
  12. Crit Rev Immunol. 2020 ;40(3): 205-224
      Macrophages are cells of the myeloid lineage with important roles not only in immune regulation and tissue repair, but also in pathological states such as autoimmune disease and cancer. A plethora of macrophage subtypes exist with distinct phenotypes and functions, not least within the tumor microenvironment (TME) of solid tumors. The abundant macrophages located within the TME are often referred to as tumor-associated macrophages (TAMs). TAMs may be pro-inflammatory with antitumor properties, or may have pro-tumor functions such as angiogenesis. Typically, TAMs are endowed with pro-tumor phenotypes, which has led to strategies to deplete or reprogram TAMs within the TME. Although historically recognized as professional antigen presenting cells (APCs), macrophages are often considered inferior in their abilities to process and present antigens in comparison with dendritic cells (DCs). Notwithstanding, this review gives an overview of the potential accessory role that macrophages might have in antigen processing and presentation to T cells within the TME, with implications for the design of novel immunotherapies.
  13. Front Oncol. 2020 ;10 598817
      The development and application of whole genome sequencing technology has greatly broadened our horizons on the capabilities of long non-coding RNAs (lncRNAs). LncRNAs are more than 200 nucleotides in length and lack protein-coding potential. Increasing evidence indicates that lncRNAs exert an irreplaceable role in tumor initiation, progression, as well as metastasis, and are novel molecular biomarkers for diagnosis and prognosis of cancer patients. Furthermore, lncRNAs and the pathways they influence might represent promising therapeutic targets for a number of tumors. Here, we discuss the recent advances in understanding of the specific regulatory mechanisms of lncRNAs. We focused on the signal, decoy, guide, and scaffold functions of lncRNAs at the epigenetic, transcription, and post-transcription levels in cancer cells. Additionally, we summarize the research strategies used to investigate the roles of lncRNAs in tumors, including lncRNAs screening, lncRNAs characteristic analyses, functional studies, and molecular mechanisms of lncRNAs. This review will provide a short but comprehensive description of the lncRNA functions in tumor development and progression, thus accelerating the clinical implementation of lncRNAs as tumor biomarkers and therapeutic targets.
    Keywords:  cancer; long non-coding RNA; mechanism of action; research strategies; therapeutic targets
  14. Methods Mol Biol. 2021 ;2261 323-343
      Chromatin immunoprecipitation (ChIP) is a method used to examine the genomic localization of a target of interest (e.g., proteins, protein posttranslational modifications, or DNA elements). As ChIP provides a snapshot of in vivo DNA-protein interactions, it lends insight to the mechanisms of gene expression and genome regulation. This chapter provides a detailed protocol focused on native-ChIP (N-ChIP), a robust approach to profile stable DNA-protein interactions. We also describe best practices for ChIP , including defined controls to ensure specific and efficient target enrichment and methods for data normalization.
    Keywords:  Antibody specificity; ChIP; ChIP normalization; Chromatin immunoprecipitation; Histone PTMs; Recombinant nucleosomes; Semisynthetic nucleosomes; Spike-in controls
  15. Oncogenesis. 2021 Jan 08. 10(1): 2
      Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high cells proliferate, EWS-FLI1low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.
  16. J Cell Biol. 2021 Feb 01. pii: e201807163. [Epub ahead of print]220(2):
      Cancer cells develop strong genetic dependencies, enabling survival under oncogenic stress. MYC is a key oncogene activated across most cancers, and identifying associated synthetic lethality or sickness can provide important clues about its activity and potential therapeutic strategies. On the basis of previously conducted genome-wide screenings in MCF10A cells expressing MYC fused to an estrogen receptor fragment, we identified UVSSA, a gene involved in transcription-coupled repair, whose knockdown or knockout decreased cell viability when combined with MYC expression. Synthetic sick interactions between MYC expression and UVSSA down-regulation correlated with ATM/CHK2 activation, suggesting increased genome instability. We show that the synthetic sick interaction is diminished by attenuating RNA polymerase II (RNAPII) activity; yet, it is independent of UV-induced damage repair, suggesting that UVSSA has a critical function in regulating RNAPII in the absence of exogenous DNA damage. Supporting this hypothesis, RNAPII ChIP-seq revealed that MYC-dependent increases in RNAPII promoter occupancy are reduced or abrogated by UVSSA knockdown, suggesting that UVSSA influences RNAPII dynamics during MYC-dependent transcription. Taken together, our data show that the UVSSA complex has a significant function in supporting MYC-dependent RNAPII dynamics and maintaining cell survival during MYC addiction. While the role of UVSSA in regulating RNAPII has been documented thus far only in the context of UV-induced DNA damage repair, we propose that its activity is also required to cope with transcriptional changes induced by oncogene activation.
  17. Future Oncol. 2021 Jan 06.
      TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, can induce apoptosis in cancer cells, sparing normal cells when bound to its associated death receptors (DR4/DR5). This unique mechanism makes TRAIL a potential anticancer therapeutic agent. However, clinical trials of recombinant TRAIL protein and TRAIL receptor agonist monoclonal antibodies have shown disappointing results due to its short half-life, poor pharmacokinetics and the resistance of the cancer cells. This review summarizes TRAIL-induced apoptotic and survival pathways as well as mechanisms leading to apoptotic resistance. Recent development of methods to overcome cancer cell resistance to TRAIL-induced apoptosis, such as protein modification, combination therapy and TRAIL-based gene therapy, appear promising. We also discuss the challenges and opportunities in the development of TRAIL-based therapies for the treatment of human cancers.
    Keywords:  TNFRSF superfamily; TRAIL; TRAIL-R; apoptosis; cancer therapy; clinical trials; death receptors; decoy receptors; gene therapy; resistance
  18. Genes Dev. 2021 Jan 01. 35(1-2): 40-58
      Major advances in the chromatin and epigenetics fields have uncovered the importance of core histones, histone variants and their post-translational modifications (PTMs) in modulating chromatin structure. However, an acutely understudied related feature of chromatin structure is the role of linker histone H1. Previous assumptions of the functional redundancy of the 11 nonallelic H1 variants are contrasted by their strong evolutionary conservation, variability in their potential PTMs, and increased reports of their disparate functions, sub-nuclear localizations and unique expression patterns in different cell types. The commonly accepted notion that histone H1 functions solely in chromatin compaction and transcription repression is now being challenged by work from multiple groups. These studies highlight histone H1 variants as underappreciated facets of chromatin dynamics that function independently in various chromatin-based processes. In this review, we present notable findings involving the individual somatic H1 variants of which there are seven, underscoring their particular contributions to distinctly significant chromatin-related processes.
    Keywords:  H1; chromatin; histone; histone variant; linker histone
  19. Expert Opin Ther Targets. 2021 Jan 08. 1-10
      Introduction: Translesion synthesis (TLS) is a DNA damage tolerance (DDT) mechanism that employs error-prone polymerases to bypass replication blocking DNA lesions, contributing to a gain in mutagenesis and chemo-resistance. However, recent findings illustrate an emerging role for TLS in replication gap suppression (RGS), distinct from its role in post-replication gap filling. Here, TLS protects cells from replication stress (RS)-induced toxic single-stranded DNA (ssDNA) gaps that accumulate in the wake of active replication. Intriguingly, TLS-mediated RGS is specifically observed in several cancer cell lines and contributes to their survival. Thus, targeting TLS has the potential to uniquely eradicate tumors without harming non-cancer tissues. Areas Covered: This review provides an innovative perspective on the role of TLS beyond its canonical function of lesion bypass or post-replicative gap filling. We provide a comprehensive analysis that underscores the emerging role of TLS as a cancer adaptation necessary to overcome the replication stress response (RSR), an anti-cancer barrier. Expert Opinion: TLS RGS is critical for tumorigenesis and is a new hallmark of cancer. Although the exact mechanism and extent of TLS dependency in cancer is still emerging, TLS inhibitors have shown promise as an anti-cancer therapy in selectively targeting this unique cancer vulnerability.
    Keywords:  DNA lesion bypass; Translesion synthesis (TLS); cancer and cancer therapeutics; mutagenesis; oncogene-induced replication stress; replication gap suppression (RGS); replication stress response (RSR); ssDNA gaps
  20. Theranostics. 2021 ;11(3): 1016-1030
      Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.
    Keywords:  Tumor-associated macrophage; metabolism; tumor immunotherapy; tumor microenvironment
  21. Cancer Chemother Pharmacol. 2021 Jan 05.
      PURPOSE: The ERCC1-XPF 5'-3' DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs.METHODS: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein-protein interaction in cancer cells using proximity ligation assay.
    RESULTS: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions.
    CONCLUSION: Our results confirm the feasibility of the approach of targeting the protein-protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds.
    Keywords:  Cancer; Chemical synthesis; DNA repair; Protein–protein interaction
  22. Cureus. 2020 Dec 03. 12(12): e11870
      Adamantinoma-like Ewing sarcoma (ALES) is a rare variant of Ewing sarcoma. It demonstrates heterogeneous morphologic pattern and complex immunophenotypic profile, with a peculiar combination of epithelial and neuroendocrine differentiation. ALES is rarely reported in the head and neck areas, including the parotid salivary gland. Till now, only 10 cases of ALES have been reported in the salivary glands. Herein, we report two cases of ALES involving the parotid gland, adding some valuable insight to the recently reported cases at this site.
    Keywords:  adamantinoma; ewing; parotid gland; salivary gland; sarcoma
  23. Cancers (Basel). 2020 Dec 30. pii: E79. [Epub ahead of print]13(1):
      Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8-18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.
    Keywords:  ATM; DNA damage; PTEN; ROS; ionising radiation; prostate cancer
  24. Diabetes. 2021 Jan 06. pii: db200096. [Epub ahead of print]
      Elucidation of mechanisms that govern lipid storage, oxidative stress and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter 1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA-sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance and type 2 diabetes.
  25. Circ Res. 2021 Jan 08. 128(1): 136-149
      The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.
    Keywords:  adiponectin; cardiovascular diseases; hypoadiponectinemia; leptin; obesity
  26. Nucleic Acids Res. 2021 Jan 07. pii: gkaa1273. [Epub ahead of print]
      Well-differentiated liposarcoma (WDLPS) is a malignant neoplasia hard to diagnose and treat. Its main molecular signature is amplification of the MDM2-containing genomic region. The MDM2 oncogene is the master regulator of p53: its overexpression enhances p53 degradation and inhibits apoptosis, leading to the tumoral phenotype. Here, we show that the MDM2 inducible promoter G-rich region folds into stable G-quadruplexes both in vitro and in vivo and it is specifically recognized by cellular helicases. Cell treatment with G-quadruplex-ligands reduces MDM2 expression and p53 degradation, thus stimulating cancer cell cycle arrest and apoptosis. Structural characterization of the MDM2 G-quadruplex revealed an extraordinarily stable, unique four-tetrad antiparallel dynamic conformation, amenable to selective targeting. These data indicate the feasibility of an out-of-the-box G-quadruplex-targeting approach to defeat WDLPS and all tumours where restoration of wild-type p53 is sought. They also point to G-quadruplex-dependent genomic instability as possible cause of MDM2 expansion and WDLPS tumorigenesis.
  27. Int J Obes (Lond). 2021 Jan 07.
      OBJECTIVE: Both obesity and insulin resistance are characterized by severe long-term changes in the expression of many genes of importance in the regulation of metabolism. Because these changes occur throughout life, as a result of external factors, the disorders of gene expression could be epigenetically regulated.MATERIALS/METHODS: We analyzed the relationship between obesity and insulin resistance in enrolled patients by means of evaluation of the expression rate of numerous genes involved in the regulation of adipocyte metabolism and energy homeostasis in subcutaneous and visceral adipose tissue depots. We also investigated global and site-specific DNA methylation as one of the main regulators of gene expression. Visceral and subcutaneous adipose tissue biopsies were collected from 45 patients during abdominal surgery in an age range of 40-60 years.
    RESULTS: We demonstrated hypermethylation of PPARG, INSR, SLC2A4, and ADIPOQ promoters in obese patients with insulin resistance. Moreover, the methylation rate showed a negative correlation with the expression of the investigated genes. More, we showed a correlation between the expression of PPARG and the expression of numerous genes important for proper insulin action. Given the impact of PPARγ on the regulation of the cell insulin sensitivity through modulation of insulin pathway genes expression, hypermethylation in the PPARG promoter region may constitute one of the epigenetic pathways in the development of insulin resistance in obesity.
    CONCLUSIONS: Our research shows that epigenetic regulation through excessive methylation may constitute a link between obesity and subsequent insulin resistance.