bims-exocan 2023-02-26 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2023‒02‒26
fourteen papers selected by
Muhammad Rizwan
COMSATS University

Exosomes as a Source of Biomarkers for Gastrointestinal Cancers.
Similarities and Differences in the Protein Composition of Cutaneous Melanoma Cells and Their Exosomes Identified by Mass Spectrometry.
Exosomal miR-146b-5p derived from cancer-associated fibroblasts promotes progression of oral squamous cell carcinoma by downregulating HIPK3.
Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors.
Tumor-targeted exosomes for delivery of anticancer drugs.
Multiple Myeloma Side Population Cells Promote Dexamethasone Resistance of Main Population Cells through Exosome Metastasis of LncRNA SNHG16.
Extracellular Vesicles in Colorectal Cancer: From Tumor Growth and Metastasis to Biomarkers and Nanomedications.
Extracellular vesicles derived from lung cancer cells promote the progression of lung cancer by delivering miR-151a-5p.
The predictive value of plasma exosomal lncRNAs/mRNAs in NSCLC patients receiving immunotherapy.
Challenges and strategies: Scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy.
TGFβ carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.
The expression of Rab5 and its effect on invasion, migration and exosome secretion in triple negative breast cancer.
Expression profile of adrenomedullin and its specific receptors in liver tissues from patients with hepatocellular carcinoma and in tumorigenic cell line-secreted extracellular vesicles.
Effect of Ethanol on Exosome Biogenesis: Possible Mechanisms and Therapeutic Implications.

Cancers (Basel). 2023 Feb 16. pii: 1263. [Epub ahead of print]15(4):

Exosomes as a Source of Biomarkers for Gastrointestinal Cancers.

Jingjing Yu, Arsha Ostowari, Amber Gonda, Kiarash Mashayekhi, Farshid Dayyani, Christopher C W Hughes, Maheswari Senthil.

  Exosomes are small, lipid-bilayer bound extracellular vesicles of 40-160 nanometers in size that carry important information for intercellular communication. Exosomes are produced more by tumor cells than normal cells and carry tumor-specific content, such as DNA, RNA, and proteins, which have been implicated in tumorigenesis, tumor progression, and treatment response. Due to the critical role of exosomes in cancer development and progression, they can be exploited to develop specific biomarkers and therapeutic targets. Since exosomes are present in various biofluids, such as blood, saliva, urine, and peritoneal fluid, they are ideally suited to be developed as liquid biopsy tools for early diagnosis, molecular profiling, disease surveillance, and treatment response monitoring. In the past decade, numerous studies have been published about the functional significance of exosomes in a wide variety of cancers, with a particular focus on exosome-derived RNAs and proteins as biomarkers. In this review, utilizing human studies on exosomes, we highlight their potential as diagnostic, prognostic, and predictive biomarkers in gastrointestinal cancers.

Keywords:  biomarker; exosomes; gastrointestinal cancers; liquid biopsy

DOI:  https://doi.org/10.3390/cancers15041263
Cancers (Basel). 2023 Feb 08. pii: 1097. [Epub ahead of print]15(4):

Similarities and Differences in the Protein Composition of Cutaneous Melanoma Cells and Their Exosomes Identified by Mass Spectrometry.

Magdalena Surman, Urszula Jankowska, Magdalena Wilczak, Małgorzata Przybyło.

  Intercellular transport of proteins mediated by extracellular vesicles (EVs)-exosomes and ectosomes-is one of the factors facilitating carcinogenesis. Therefore, the research on protein cargo of melanoma-derived EVs may provide a better understanding of the mechanisms involved in melanoma progression and contribute to the development of alternative biomarkers. Proteomic data on melanoma-derived EVs are very limited. The shotgun nanoLC-MS/MS approach was applied to analyze the protein composition of primary (WM115, WM793) and metastatic (WM266-4, WM1205Lu) cutaneous melanoma cells and exosomes released by them. All cells secreted homogeneous populations of exosomes that shared a characteristic set of proteins. In total, 3514 and 1234 unique proteins were identified in melanoma cells and exosomes, respectively. Gene ontology analysis showed enrichment in several cancer-related categories, including cell proliferation, migration, negative regulation of apoptosis, and angiogenesis. The obtained results broaden our knowledge on the role of selected proteins in exosome biology, as well as their functional role in the development and progression of cutaneous melanoma. The results may also inspire future studies on the clinical potential of exosomes.

Keywords:  LC-MS/MS; cancer; exosomes; extracellular vesicles; melanoma; proteomics

DOI:  https://doi.org/10.3390/cancers15041097
Cell Signal. 2023 Feb 20. pii: S0898-6568(23)00049-9. [Epub ahead of print] 110635

Exosomal miR-146b-5p derived from cancer-associated fibroblasts promotes progression of oral squamous cell carcinoma by downregulating HIPK3.

Lihong He, Jiaxin Guo, Zhaona Fan, Shiwen Yang, Chi Zhang, Bin Cheng, Juan Xia.

  OBJECTIVES: Cancer-associated fibroblasts (CAFs) are vital constituents of the tumor microenvironment (TME) and play a predominant role in oral squamous cell carcinoma (OSCC) progression. We aimed to investigate the effect and mechanism of exosomal miR-146b-5p derived from CAFs on the malignant biological behavior of OSCC.MATERIALS AND METHODS: Illumina small RNA (sRNA) sequencing was conducted to determine the differential expression patterns of microRNAs (miRNAs) in exosomes derived from CAFs and normal fibroblasts (NFs). Transwell and cell counting kit-8 (CCK-8) assays and xenograft tumor models in nude mice were used to investigate the effect of CAF exosomes and miR-146b-p on the malignant biological behavior of OSCC. Reverse transcription quantitative real-time PCR (qRT-PCR), luciferase reporter, western blotting (WB) and immunohistochemistry assays were employed to investigate the underlying mechanisms involved in CAF exosomes that promote OSCC progression.
RESULTS: We demonstrated that CAF-derived exosomes were taken up by OSCC cells and enhanced the proliferation, migration, and invasion ability of OSCC. Compared with NFs, the expression of miR-146b-5p was increased in exosomes and their parent CAFs. Further studies showed that the decreased expression of miR-146b-5p inhibited the proliferation, migration and invasion ability of OSCC cells in vitro and the growth of OSCC cells in vivo. Mechanistically, miR-146b-5p overexpression led to the suppression of HIKP3 by directly targeting the 3'-UTR of HIPK3, as confirmed by luciferase assay. Reciprocally, HIPK3 knockdown partially reversed the inhibitory effect of the miR-146b-5p inhibitor on the proliferation, migration, and invasion ability of OSCC cells and restored their malignant phenotype.
CONCLUSIONS: Our results revealed that CAF-derived exosomes contained higher levels of miR-146b-5p than NFs, and miR-146b-5p overexpression in exosomes promoted the malignant phenotype of OSCC by targeting HIPK3. Therefore, inhibiting exosomal miR-146b-5p secretion may be a promising therapeutic modality for OSCC.

Keywords:  Carcinoma-associated fibroblast; Exosome; HIPK3; Oral squamous cell carcinoma; miR-146b-5p

DOI:  https://doi.org/10.1016/j.cellsig.2023.110635
Cancers (Basel). 2023 Feb 18. pii: 1307. [Epub ahead of print]15(4):

Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors.

Barnabas Irmer, Suganja Chandrabalan, Lukas Maas, Annalen Bleckmann, Kerstin Menck.

  Extracellular vesicles (EVs) are secreted by all living cells and are ubiquitous in every human body fluid. They are quite heterogeneous with regard to biogenesis, size, and composition, yet always reflect their parental cells with their cell-of-origin specific cargo loading. Since numerous studies have demonstrated that EV-associated proteins, nucleic acids, lipids, and metabolites can represent malignant phenotypes in cancer patients, EVs are increasingly being discussed as valuable carriers of cancer biomarkers in liquid biopsy samples. However, the lack of standardized and clinically feasible protocols for EV purification and characterization still limits the applicability of EV-based cancer biomarker analysis. This review first provides an overview of current EV isolation and characterization techniques that can be used to exploit patient-derived body fluids for biomarker quantification assays. Secondly, it outlines promising tumor-specific EV biomarkers relevant for cancer diagnosis, disease monitoring, and the prediction of cancer progression and therapy resistance. Finally, we summarize the advantages and current limitations of using EVs in liquid biopsy with a prospective view on strategies for the ongoing clinical implementation of EV-based biomarker screenings.

Keywords:  biomarker; cancer; extracellular vesicles; liquid biopsy

DOI:  https://doi.org/10.3390/cancers15041307
Cancer Lett. 2023 Feb 21. pii: S0304-3835(23)00044-7. [Epub ahead of print] 216093

Tumor-targeted exosomes for delivery of anticancer drugs.

Rajeswari Raguraman, Dhaval Bhavsar, Dongin Kim, Xiaoyu Ren, Vassilios Sikavitsas, Anupama Munshi, Rajagopal Ramesh.

  Exosomes are small phospholipid bilayer vesicles that are naturally produced by all living cells, both prokaryotes and eukaryotes. The exosomes due to their unique size, reduced immunogenicity, and their ability to mimic synthetic liposomes in carrying various anticancer drugs have been tested as drug delivery vehicles for cancer treatment. An added advantage of developing exosomes as a drug carrier is the ease of manipulating their intraluminal content and their surface modification to achieve tumor-targeted drug delivery. In the past ten-years, there has been exponential increase in the number of exosome-related studies in cancer. Pre-clinical studies demonstrate exosomes-mediated delivery of chemotherapeutics, biologicals and natural products produce potent anticancer activity both, in vitro and in vivo. In contrast, the number of exosome-based clinical trials are few due to challenges in the manufacturing and scalability related to large-scale production of exosomes and their storage and stability. Herein, we discuss recent advances in exosome-based drug delivery for cancer treatment in preclinical and clinical studies and conclude with challenges to be overcome for translating a larger number of exosome-based therapies into the clinic.

Keywords:  Drug delivery; Exosomes; Extracellular vesicles; Nanomedicine; Targeting

DOI:  https://doi.org/10.1016/j.canlet.2023.216093
J Oncol. 2023 ;2023 5135445

Multiple Myeloma Side Population Cells Promote Dexamethasone Resistance of Main Population Cells through Exosome Metastasis of LncRNA SNHG16.

Xi Yang, Zenghua Lin, Haiyan Liu, Xinfeng Wang, Hong Liu.

Background: The emergence of dexamethasone (Dex) resistance limits its efficacy. Side population (SP) cells in MM have strong tumorigenicity. Nevertheless, the detailed effect by which SP cells regulate Dex resistance in MP cells has not been completely verified and needs to be further investigated.Methods: SP and MP cells were sorted from RPMI-8226. mRNA expression and cell viability were analyzed using quantitative real-time PCR (qRT-PCR) and MTS assays, respectively. The presence of exosomal lncRNA SNHG16 was verified by transmission electron microscopy, differential ultracentrifugation, and qRT-PCR. Protein expression levels were measured using western blotting. Gain or loss function analyses were performed to demonstrate the role of SNHG16 in the Dex resistance of MP cells.
Results: Dex resistance of SP cells was remarkably stronger than that of MP cells. Compared with MP cells, the survival rate and Dex resistance of MP cells cotreated with SP cell-derived exosomes were increased. SNHG16 expression was significantly enhanced in SP cell-derived exosomes compared to MP cell-derived exosomes. SNHG16 expression was remarkably increased in MP cells transfected with OE-SNHG16 vectors, and Dex resistance of MP cells was enhanced. When SNHG16 was silenced in SP cells, the SNHG16 expression was downregulated in both SP cells and SP cell-derived exosomes. SNHG16 expression and Dex resistance were both remarkably downregulated in MP cells treated with SP-si-SNHG16-exosomes compared to MP cells treated with SP-si-NC-exosomes.
Conclusion: MM SP cells promote Dex resistance in MP cells through exosome metastasis of SNHG16.

DOI: https://doi.org/10.1155/2023/5135445
Cancers (Basel). 2023 Feb 09. pii: 1107. [Epub ahead of print]15(4):

Extracellular Vesicles in Colorectal Cancer: From Tumor Growth and Metastasis to Biomarkers and Nanomedications.

Larissa Kotelevets, Eric Chastre.

  Colorectal cancer (CRC) is a leading public health concern due to its incidence and high mortality rates, highlighting the requirement of an early diagnosis. Evaluation of circulating extracellular vesicles (EVs) might constitute a noninvasive and reliable approach for CRC detection and for patient follow-up because EVs display the molecular features of the cells they originate. EVs are released by almost all cell types and are mainly categorized as exosomes originating from exocytosis of intraluminal vesicles from multivesicular bodies, ectosomes resulting from outward budding of the plasma membrane and apoptotic bodies' ensuing cell shrinkage. These vesicles play a critical role in intercellular communications during physiological and pathological processes. They facilitate CRC progression and premetastatic niche formation, and they enable transfer of chemotherapy resistance to sensitive cells through the local or remote delivery of their lipid, nucleic acid and protein content. On another note, their stability in the bloodstream, their permeation in tissues and their sheltering of packaged material make engineered EVs suitable vectors for efficient delivery of tracers and therapeutic agents for tumor imaging or treatment. Here, we focus on the physiopathological role of EVs in CRCs, their value in the diagnosis and prognosis and ongoing investigations into therapeutic approaches.

Keywords:  colorectal cancer; diagnosis; ectosomes; exosomes; extracellular vesicles; lncRNA; metastasis; miRNA; microvesicles; nanomedicine

DOI:  https://doi.org/10.3390/cancers15041107
Exp Cell Res. 2023 Feb 22. pii: S0014-4827(23)00073-3. [Epub ahead of print] 113526

Extracellular vesicles derived from lung cancer cells promote the progression of lung cancer by delivering miR-151a-5p.

Huoli Hu, Lei Jiang, Xiuhua Kang, Li Zhang, Shanggan Zeng.

  Extracellular vesicles (EVs) participate in the occurrence and development of lung cancer. MiR-151a-5p has been reported to be highly expressed in the tumor tissues of lung cancer. The aim of this work was to investigate whether EVs can affect lung cancer progression by delivering miR-151a-5p. In this work, we found that miR-151a-5p was highly expressed in serum of lung cancer patients. Up-regulation of miR-151a-5p and down-regulation of Nedd4-binding partner-1 (N4BP1) were observed in lung cancer cell lines. The expression of miR-151a-5p was also increased in H520-derived EVs. H520-derived EVs promoted cell proliferation, inhibited apoptosis of H520 cells by delivering miR-151a-5p. EVs containing miR-151a-5p repressed E-cadherin expression and elevated N-cadherin and Vimentin expression to impede epithelial-mesenchymal transition (EMT) of H520 cells. Additionally, the interaction between miR-151a-5p and N4BP1 was verified by luciferase reporter assay, showing that miR-151a-5p interacted with N4BP1. MiR-151a-5p repressed N4BP1 expression by interacting with N4BP1. EVs containing miR-151a-5p promoted malignant phenotypes of H520 cells by targeting N4BP1. Finally, a tumor-bearing mouse model was constructed by inoculation of H520 cells with miR-151a-5p overexpression or knockdown. Overexpression of miR-151a-5p accelerated tumor growth of lung cancer in vivo, and repressed N4BP1 expression in the tumor tissues. Knockdown of miR-151a-5p caused opposite results. In conclusion, this work demonstrated that lung cancer cell-derived EVs secreted miR-151a-5p to promote cell proliferation, and inhibit apoptosis and EMT of lung cancer cells by targeting N4BP1, thereby accelerating lung cancer progression. Thus, this study suggests that EVs-derived miR-151a-5p may be a potential target for lung cancer treatment.

Keywords:  Extracellular vesicles; Lung cancer; Malignant progression; N4BP1; miR-151a-5p

DOI:  https://doi.org/10.1016/j.yexcr.2023.113526
Adv Med Sci. 2023 Feb 17. pii: S1896-1126(23)00003-2. [Epub ahead of print]68(1): 86-93

The predictive value of plasma exosomal lncRNAs/mRNAs in NSCLC patients receiving immunotherapy.

Yue Wang, Shuhui Cao, Jingwen Li, Yao Zhang, Xuxinyi Ling, Lincheng Zhang, Yan Zhou, Hua Zhong.

  PURPOSE: There is an urgent need to explore the use of plasma-derived exosomal long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) as potential biomarkers to select the most suitable patient population to receive immunotherapy for advanced NSCLC with no actionable molecular markers.PATIENTS AND METHODS: In the present study, 7 patients with advanced NSCLC who received nivolumab were enrolled for molecular studies. Plasma-derived exosomal lncRNAs/mRNAs expression profiles differed between patients exhibiting differential immunotherapy efficacy.
RESULTS: In the non-responders, 299 differentially expressed exosomal mRNAs and 154 lncRNAs were significantly upregulated. In GEPIA2, 10 mRNAs were upregulated in the NSCLC patients compared to that of the normal population. The up-regulation of CCNB1 related to the cis-regulation of lnc-CENPH-1 and lnc-CENPH-2. KPNA2, MRPL3, NET1 and CCNB1 were trans-regulated by lnc-ZFP3-3. In addition, IL6R exhibited a trend of increased expression in the non-responders at baseline, and this expression was further downregulated after treatment in responders. The association between CCNB1 with lnc-CENPH-1 and lnc-CENPH-2, as well as the lnc-ZFP3-3-TAF1 pair, may represent potential biomarkers of poor immunotherapy efficacy. Patients may obtain increased effector T cell function when IL6R is suppressed by immunotherapy.
CONCLUSIONS: Our study suggests that plasma-derived exosomal lncRNA and mRNA expression profiles differ between responders and non-responders to nivolumab immunotherapy. Lnc-ZFP3-3-TAF1-CCNB1 pair and IL6R might be key factors predicting efficiency of immunotherapy. Large scale clinical studies seem warranted to further validate the potential of plasma-derived exosomal lncRNAs and mRNAs as a biomarker to aid the selection of NSCLC patients for nivolumab immunotherapy.

Keywords:  Exosomes; Immunotherapy; Lung cancer; lncRNA; mRNA

DOI:  https://doi.org/10.1016/j.advms.2023.01.003
Life Sci. 2023 Feb 22. pii: S0024-3205(23)00158-3. [Epub ahead of print] 121524

Challenges and strategies: Scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy.

Wei Pan, Hongyuan Chen, Aijun Wang, Fengshan Wang, Xinke Zhang.

  Exosomes are small membrane vesicles secreted by most cell types, and widely exist in cell supernatants and various body fluids. They can transmit numerous bioactive elements, such as proteins, nucleic acids, and lipids, to affect the gene expression and function of recipient cells. Mesenchymal stem cells (MSCs) have been confirmed to be a potentially promising therapy for tissue repair and regeneration. Accumulating studies demonstrated that the predominant regenerative paradigm of MSCs transplantation was the paracrine effect but not the differentiation effect. Exosomes secreted by MSCs also showed similar therapeutic effects as their patenting cells and were considered to be used for cell-free regenerative medicine. However, the inefficient and limited production has hampered their development for clinical translation. In this review, we summarize potential methods to efficiently promote the yield of exosomes. We mainly focus on engineering the process of exosome biogenesis and secretion, altering the cell culture conditions, cell expansion through 3D dynamic culture and the isolation of exosomes. In addition, we also discuss the application of MSCs-derived exosomes as therapeutics in disease treatment.

Keywords:  Cell-free therapy; Clinical translation; Exosomes; Mesenchymal stem cells; Scalable approach; Tissue repair and regeneration

DOI:  https://doi.org/10.1016/j.lfs.2023.121524
Br J Cancer. 2023 Feb 21.

TGFβ carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.

Nils Ludwig, Saigopalakrishna S Yerneni, Malgorzata Harasymczuk, Mirosław J Szczepański, Alicja Głuszko, Wojciech Kukwa, Theresa Jordan, Gerrit Spanier, Juergen Taxis, Steffen Spoerl, Johannes K Meier, Cynthia S Hinck, Phil G Campbell, Torsten E Reichert, Andrew P Hinck, Theresa L Whiteside.

OBJECTIVES: Contributions of TGFβ to cancer progression are well documented. However, plasma TGFβ levels often do not correlate with clinicopathological data. We examine the role of TGFβ carried in exosomes isolated from murine and human plasma as a contributor to disease progression in head and neck squamous cell carcinoma (HNSCC).MATERIALS AND METHODS: The 4-nitroquinoline-1-oxide (4-NQO) mouse model was used to study changes in TGFβ expression levels during oral carcinogenesis. In human HNSCC, TGFβ and Smad3 protein expression levels and TGFB1 gene expression were determined. Soluble TGFβ levels were evaluated by ELISA and TGFβ bioassays. Exosomes were isolated from plasma using size exclusion chromatography, and TGFβ content was quantified using bioassays and bioprinted microarrays.
RESULTS: During 4-NQO carcinogenesis, TGFβ levels in tumour tissues and in serum increased as the tumour progressed. The TGFβ content of circulating exosomes also increased. In HNSCC patients, TGFβ, Smad3 and TGFB1 were overexpressed in tumour tissues and correlated with increased soluble TGFβ levels. Neither TGFβ expression in tumours nor levels of soluble TGFβ correlated with clinicopathological data or survival. Only exosome-associated TGFβ reflected tumour progression and correlated with tumour size.
CONCLUSIONS: Circulating TGFβ+ exosomes in the plasma of patients with HNSCC emerge as potential non-invasive biomarkers of disease progression in HNSCC.

DOI: https://doi.org/10.1038/s41416-023-02184-3
Korean J Physiol Pharmacol. 2023 Mar 01. 27(2): 157-165

The expression of Rab5 and its effect on invasion, migration and exosome secretion in triple negative breast cancer.

Lei Qiao, Chao Dong, Jiaojiao Zhang, Gang Sun.

  Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and current therapeutic strategies are limited in their effectiveness. The expressions of Rab5 and the M2 tumor-associated macrophage marker CD163 in tissues were detected by Western blot. The migration and invasion of cells were determined using a Transwell assay. The expressions of the exosome markers were evaluated by Western blot. The polarization of human macrophages (THP-1) was determined by incubation of THP-1 cells with conditioned medium or exosomes collected from MDA-MB-231 cells with indicated transfections or by a coculture system of THP-1 and MDA-MB-231 cells. The M1 and M2 macrophage markers were evaluated by qRT-PCR. The expression of Rab5 in TNBC was significantly higher than that in normal breast tissue. Rab5 expressions in triple-negative and luminal A breast cancer were higher than those in other molecular subtypes. Higher CD163 expression was observed in triple-negative breast cancer and in triple-negative and luminal B subtypes. Rab5 knockdown suppressed but Rab5 overexpression promoted the migration and invasion capacity of MDA-MB-231 cells. The levels of CD63 and CD9 in the medium of Rab5 knockdown cells were lower than those in control cells, whereas higher levels of CD63 and CD9 were observed in Rab5 overexpression cells. Rab5 knockdown decreased the excretion but did not alter the diameter of the exosomes. Knockdown of Rab5 facilitated the anti-tumor polarization of macrophages, which was partially reversed by Rab5 overexpression. Therefore, Rab5 is expected to be a potential therapeutic target for triple-negative breast cancer.

Keywords:  Exosomes; Rab5 GTP-binding proteins; Triple-negative breast cancer; Tumor-associated macrophages

DOI:  https://doi.org/10.4196/kjpp.2023.27.2.157
Pathol Res Pract. 2023 Feb 20. pii: S0344-0338(23)00083-3. [Epub ahead of print]243 154383

Expression profile of adrenomedullin and its specific receptors in liver tissues from patients with hepatocellular carcinoma and in tumorigenic cell line-secreted extracellular vesicles.

Manuela Cabiati, Melania Gaggini, Paolo De Simone, Costanza Salvadori, Serena Del Turco, Chiara Caselli, Antonella Cecchettini, Silvia Del Ry.

  The transcriptional profile of adrenomedullin (AM), a new metastasis-related factor involved in hepatocellular carcinoma (HCC), and its specific receptors (CLR, RAMP1, RAMP3) were evaluated in liver tissues of HCV-positive HCC subjects undergoing liver transplantation (LR) and in donors (LD). AM and its specific receptor expression were also assessed in extracellular vesicles (EVs) secreted by tumorigenic (HepG2) and non-tumorigenic (WRL68) cells by Real-Time PCR. AM expression resulted significantly elevated in LR concerning LD (p = 0.0038) and, for the first time, significantly higher levels in HCC patients as a function of clinical severity (MELD score), were observed. RAMP3 and CLR expression increased in LR as a function of clinical severity while RAMP1 decreased. Positive correlations were found among AM, its receptors, and apoptotic markers. No AM mRNA expression difference was observed between HepG2 and WRL68 EVs. RAMP1 and RAMP3 resulted lower in HepG2 concerning WRL68 while significantly higher levels were observed for CLR. While results at tissue level characterize AM as a regulator of carcinogenesis-tumor progression, those obtained in EVs do not indicate AM as a target candidate, neither as a pathological biomarker nor as a marker involved in cancer therapy.

Keywords:  Adrenomedullin; Calcitonin receptor like receptor (CLR); Extracellular vesicles; HCC; RAMP1; RAMP3; Real-Time PCR

DOI:  https://doi.org/10.1016/j.prp.2023.154383
Biomolecules. 2023 Jan 24. pii: 222. [Epub ahead of print]13(2):

Effect of Ethanol on Exosome Biogenesis: Possible Mechanisms and Therapeutic Implications.

Vaishnavi Sundar, Viswanathan Saraswathi.

  Most eukaryotic cells, including hepatocytes, secrete exosomes into the extracellular space, which are vesicles facilitating horizontal cell-to-cell communication of molecular signals and physiological cues. The molecular cues for cellular functions are carried by exosomes via specific mRNAs, microRNAs, and proteins. Exosomes released by liver cells are a vital part of biomolecular communication in liver diseases. Importantly, exosomes play a critical role in mediating alcohol-associated liver disease (ALD) and are potential biomarkers for ALD. Moreover, alcohol exposure itself promotes exosome biogenesis and release from the livers of humans and rodent models. However, the mechanisms by which alcohol promotes exosome biogenesis in hepatocytes are still unclear. Of note, alcohol exposure leads to liver injury by modulating various cellular processes, including autophagy, ER stress, oxidative stress, and epigenetics. Evidence suggests that there is a link between each of these processes with exosome biogenesis. The aim of this review article is to discuss the interplay between ethanol exposure and these altered cellular processes in promoting hepatocyte exosome biogenesis and release. Based on the available literature, we summarize and discuss the potential mechanisms by which ethanol induces exosome release from hepatocytes, which in turn leads to the progression of ALD.

Keywords:  alcohol-associated liver disease; cirrhosis; ethanol; exosomes; hepatocytes

DOI:  https://doi.org/10.3390/biom13020222