Iman Ahmed

Background: Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and is among the leading causes of cancer-related death.¹ HCC is a hypervascular solid tumor that requires neoangiogenesis in order to proliferate.² There is a growing body of research on tumor-derived exosomes and their role in facilitating communication between HCC cells and the surrounding microenvironment. Exosomes are nanometer-sized endocytic vesicles that can be physiologic or pathologic and are involved in the regulation of cellular processes, including angiogenesis, metastasis, and EMT.³ In HCC-derived exosomes, miRNA-21 and VASN are upregulated and have been proposed as diagnostic markers and therapeutic targets.^4,5 In human HCC cell lines (SNU-449, HepG2, and Hep3B), increased miR-21 expression is associated with reduced expression of the tumor suppressor gene PTEN.⁶ Furthermore, HCC-derived VASN has been associated with STAT-3 signaling in mouse models, as VASN knockout led to reduced STAT-3 phosphorylation and decreased expression of downstream matrix metalloproteinases and cyclin-dependent kinases.⁵  The links between exosomal components and cell-signaling pathways involved in cancer progression highlight the potential of exosome-associated molecules like miR-21 and VASN as key mediators of HCC progression and promising targets for future therapeutic intervention.

Objective: In this review, we explore the cellular signaling pathways through which exosomal components miRNA-21 and VASN impact HCC tumor progression, and highlight literature regarding their potential role in HCC diagnosis and treatment.

Search Methods: An online search in the PubMed database was conducted from 2015 to 2025 using the following keywords/Phrases: “Hepatocellular Carcinoma”, “Exosomes and HCC”, and “Exosomal Components”.

Results: A study on HBV-mediated HCC patients undergoing liver transplantation found that compared with nonrecurrent patients, the expression level of miR-21 was 3.54-fold higher in patients with recurrence during a 5-year follow-up visit (P = .004).⁴   Furthermore, researchers used a multivariate Cox regression to evaluate the expression profile of miR-21 and other upregulated exosome-derived components. The analysis showed that a higher expression level of miR-21 was a prognostic indicator for the recurrence probability of patients with HBV-mediated HCC patients (P = .002).⁴ Additionally, a study examining the capability of HCC cells to convert hepatic stellate cells to cancer-associated fibroblasts found that miRNA-21 was correlated with poor prognosis. High miRNA-21 expression predicted poor overall survival and disease-free survival of HCC patients.³ VASN is being discussed as a therapeutic target for HCC. A novel niclosamide prodrug (NIC-PS) was designed to directly bind and suppress VASN, suppressing TGFβ signaling and reducing SMAD2/3 phosphorylation.⁷ NIC-PS is a water-soluble, orally bioavailable NIC prodrug that overcomes NIC’s clinical limitations and enhances anti-tumor efficacy. Researchers demonstrated an enhanced efficacy of NIC-PS in combination with sorafenib and anti-PD-L1 therapies.⁷

Conclusion: Understanding the role that exosomal components play in cancer signaling pathways is important for evaluating their use in hepatocellular carcinoma treatment. Ultimately, these studies establish miRNA-21 as a prognostic indicator and VASN as a novel drug target for HCC. With regards to Vasorin and NIC-PS, more research is needed to evaluate NIC’s binding sites and interaction mechanisms with VASN, and also to refine dosages and regimens to optimize therapeutic outcomes for HCC treatment with NIC-PS safely. Another potential area for future research is the development of a novel scoring system incorporating miRNA-21 as a biomarker to detect recurrence in HBV-related HCC patients after liver transplantation.⁴

Works Cited:

1. Lee Y-T, Tran BV, Wang JJ, et al. The role of extracellular vesicles in disease progression and detection of hepatocellular carcinoma. Cancers. 2021;13(12):3076. doi:10.3390/cancers13123076
2. Huang A, Dong J, Li S, et al. Exosomal transfer of Vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells. International Journal of Biological Sciences. 2015;11(8):961-969. doi:10.7150/ijbs.11943
3. Zhou Y, Ren H, Dai B, et al. Hepatocellular carcinoma-derived exosomal MIRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. Journal of Experimental & Clinical Cancer Research. 2018;37(1). doi:10.1186/s13046-018-0965-2
4. Dundar HZ, Aksoy F, Aksoy SA, et al. Overexpression of Mir-21 is associated with recurrence in patients with hepatitis B virus–mediated hepatocellular carcinoma undergoing liver transplantation. Transplantation Proceedings. 2019;51(4):1157-1161. doi:10.1016/j.transproceed.2019.01.089
5. Wan F, Li H, Huang S, et al. Vasorin promotes proliferation and migration via STAT3 signaling and acts as a promising therapeutic target of hepatocellular carcinoma. Cellular Signalling. 2023;110:110809. doi:10.1016/j.cellsig.2023.110809
6. Cao L, Yang X, Chen Y, Zhang D, Jiang X-F, Xue P. Exosomal Mir-21 regulates the tets/PTENP1/PTEN pathway to promote hepatocellular carcinoma growth. Molecular Cancer. 2019;18(1). doi:10.1186/s12943-019-1075-2
7. Tan M, Ye W, Liu Y, et al. Niclosamide prodrug enhances oral bioavailability and targets vasorin-TGFΒ signaling in hepatocellular carcinoma. Published online October 18, 2024. doi:10.1101/2024.10.15.618538