The Role of miRNA-21 in the Metastasis of Hepatocellular Carcinoma as a Therapeutic Target
Abstract
Hepatocellular carcinoma (HCC) is a crucial health concern worldwide, representing a leading cause of cancer-related mortality and the most common form of primary liver cancer. The aggressive nature of HCC is mainly due to its high intention for invasion and metastasis, processes that are regulated by a complex network of genetic and molecular pathways. Among the critical regulators of these processes is microRNA-21 (miR-21), a small non-coding RNA that has been implicated in various oncogenic activities. This review provides a comprehensive analysis of the role of miR-21 in promoting HCC metastasis progression, with a particular focus on its interaction with key signaling pathways, including the PTEN/PI3K/AKT, PDCD4/AP-1, RECK/MMP, and TIMP-3 axes. By targeting tumor suppressors, miR-21 facilitates epithelial-to-mesenchymal transition (EMT), invasion, and metastasis of HCC cells. Understanding the molecular mechanisms regulated by miR-21 not only sheds light on the pathogenesis of HCC but also highlights possible therapeutic targets for combating this aggressive cancer.
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2. Brown JS, Amend SR, Austin RH, et al. Updating the definition of cancer. Mol Cancer Res. 2023;21(11):1142-7.
3. Amiri S, Atashi A, Azad M, et al. Upregulation of Pro-inflammatory Cytokine Genes by Parvovirus B19 in Human Bone Marrow Mesenchymal Stem Cells. Biochem Genet. 2020;58(1):63-73.
4. Azad M, Bakhshi Biniaz R, Goudarzi M, et al. Short view of leukemia diagnosis and treatment in Iran. Int J Hematol Oncol Stem Cell Res. 2015;9(2):88-94.
5. Sia D, Villanueva A, Friedman SL, et al. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152(4):745-61.
6. Sahmani M, Vatanmakanian M, Goudarzi M, et al. Microchips and their Significance in Isolation of Circulating Tumor Cells and Monitoring of Cancers. Asian Pac J Cancer Prev. 2016;17(3):879-94.
7. Maali A, Maroufi F, Sadeghi F, et al. Induced pluripotent stem cell technology: trends in molecular biology, from genetics to epigenetics. Epigenomics. 2021;13(8):631-47.
8. Amiri S, Adibzadeh S, Ghanbari S, et al. CRISPR-interceded CHO cell line development approaches. Biotechnol Bioeng. 2023;120(4):865-902.
9. Ding J, Wen Z. Survival improvement and prognosis for hepatocellular carcinoma: analysis of the SEER database. BMC Cancer. 2021;21(1):1157.
10. Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev. 2004;5(2):118-25.
11. Gravitz L. Liver cancer. Nature. 2014;516(7529):S1.
12. Sun VCY, Sarna L. Symptom management in hepatocellular carcinoma. Clin J Oncol Nurs. 2008;12(5):759-66.
13. Chen Y, Tian Z. HBV-induced immune imbalance in the development of HCC. Front Immunol. 2019;10:2048.
14. Zamor PJ, Delemos AS, Russo MW. Viral hepatitis and hepatocellular carcinoma: etiology and management. J Gastrointest Oncol. 2017;8(2):229-242.
15. Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol. 2014;20(47):17756-72.
16. Rushing BR, Selim MI. Aflatoxin B1: A review on metabolism, toxicity, occurrence in food, occupational exposure, and detoxification methods. Food Chem Toxicol. 2019;124:81-100.
17. Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103-17.
18. Saitta C, Pollicino T, Raimondo G. Obesity and liver cancer. Anna Hepatol. 2019;18(6):810-5.
19. Larsson S, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97(7):1005-8.
20. Zhang W, Xiang YB, Li HL, et al. Vegetable‐based dietary pattern and liver cancer risk: Results from the S hanghai W omen's and M en's H ealth S tudies. Cancer Sci. 2013;104(10):1353-61.
21. Fedirko V, Trichopolou A, Bamia C, et al. Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol. 2013;24(8):2166-73.
22. Liu GM, Zeng HD, Zhang CY, et al. Key genes associated with diabetes mellitus and hepatocellular carcinoma. Pathol Res Pract. 2019;215(11):152510.
23. Chakinala RC, Dawoodi S, Fabara SP, et al. Association of smoking and e-cigarette in chronic liver disease: an NHANES study. Gastroenterology Res. 2022;15(3):113-119.
24. Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-33.
25. Ma L. MicroRNA and metastasis. Adv Cancer Res. 2016;132:165-207.
26. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004.
27. Hojjatipour T, Ajeli M, Maali A, et al. Epigenetic-modifying agents: the potential game changers in the treatment of hematologic malignancies. Crit Rev Oncol Hematol. 2024;204:104498.
28. Liu Y, Xiao J, Zhao Y, et al. microRNA-216a protects against human retinal microvascular endothelial cell injury in diabetic retinopathy by suppressing the NOS2/JAK/STAT axis. Exp Mol Pathol. 2020;115:104445.
29. Nelson SR, Roche S, Cotter M, et al. Genomic Profiling and Functional Analysis of let‐7c miRNA‐mRNA Interactions Identify SOX13 to Be Involved in Invasion and Progression of Pancreatic Cancer. J Oncol. 2020;2020:2951921.
30. Azad M, Kaviani S, Soleymani M, et al. Common polymorphism’s analysis of thiopurine S-methyltransferase (TPMT) in Iranian population. Cell J. 2009; 11 (3): 311-316.
31. Fard MB, Atashi A, Amiri S, et al. Parvovirus B19 Affects Thrombopoietin and IL-11 Gene Expression in Human Bone Marrow Mesenchymal Stem Cells. Future Virol. 2021;16(8):519-26.
32. Kumarswamy R, Volkmann I, Thum T. Regulation and function of miRNA-21 in health and disease. RNA Biol. 2011;8(5):706-13.
33. Rhim J, Baek W, Seo Y, et al. From molecular mechanisms to therapeutics: understanding MicroRNA-21 in cancer. Cells. 2022;11(18):2791.
34. Zhu Q, Wang Z, Hu Y, et al. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. Oncol Rep. 2012;27(5):1660-8.
35. Fan B, Jin Y, Zhang H, et al. MicroRNA‑21 contributes to renal cell carcinoma cell invasiveness and angiogenesis via the PDCD4/c‑Jun (AP‑1) signalling pathway. Int J Oncol. 2020;56(1):178-92.
36. Monzavi N, Zargar SJ, Gheibi N, et al. Angiopoietin-like protein 8 (betatrophin) may inhibit hepatocellular carcinoma through suppressing of the Wnt signaling pathway. Iran J Basic Med Sci. 2019;22(10):1166-71.
37. Khare S, Khare T, Ramanathan R, et al. Hepatocellular carcinoma: the role of microRNAs. Biomolecules. 2022;12(5):645.
38. Xu X, Tao Y, Shan L, et al. The role of MicroRNAs in hepatocellular carcinoma. J Cancer. 2018;9(19):3557-3569.
39. Wang J, Chu Y, Xu M, et al. miR-21 promotes cell migration and invasion of hepatocellular carcinoma by targeting KLF5. Oncol Lett. 2019;17(2):2221-7.
40. Liu Q, Zhang H, Jiang X, et al. Factors involved in cancer metastasis: a better understanding to “seed and soil” hypothesis. Mol Cancer. 2017;16(1):176.
41. Mansoori S, Noei A, Maali A, et al. Recent updates on allogeneic CAR-T cells in hematological malignancies. Cancer Cell Int. 2024;24(1):304.
42. Hojjatipour T, Sharifzadeh Z, Maali A, et al. Chimeric antigen receptor-natural killer cells: a promising sword against insidious tumor cells. Hum Cell. 2023;36(6):1843-64.
43. Steeg PS. Targeting metastasis. Nat Rev Cancer. 2016;16(4):201-18.
44. Sun Y, Ma L. The emerging molecular machinery and therapeutic targets of metastasis. Trends Pharmacol Sci. 2015;36(6):349-59.
45. Veiseh O, Kievit FM, Ellenbogen RG, et al. Cancer cell invasion: treatment and monitoring opportunities in nanomedicine. Adva Drug Deliv Rev. 2011;63(8):582-96.
46. Hsu CY, Liu PH, Ho SY, et al. Metastasis in patients with hepatocellular carcinoma: prevalence, determinants, prognostic impact and ability to improve the Barcelona Clinic Liver Cancer system. Liver Int. 2018;38(10):1803-11.
47. Mohammed YHE, Thirusangu P, Vigneshwaran V, et al. The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases. Biomed Pharmacother. 2017;95:375-86.
48. Folgueras AR, Pendas AM, Sanchez LM, et al. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol. 2004;48(5-6):411-24.
49. Swetha R, Gayen C, Kumar D, et al. Biomolecular basis of matrix metallo proteinase-9 activity. Future Med Chem. 2018;10(9):1093-112.
50. Zaremba-Czogalla M, Hryniewicz-Jankowska A, Tabola R, et al. Dependent migration and invasion of triple-negative breast cancer cells. Cell Signal. 2018, 47, 27–36.
51. Pittayapruek P, Meephansan J, Prapapan O, et al. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci. 2016;17(6):868.
52. Zhao C, Yuan G, Jiang Y, et al. Capn4 contributes to tumor invasion and metastasis in gastric cancer via activation of the Wnt/β-catenin/MMP9 signalling pathways. Exp Cell Res. 2020;395(2):112220.
53. Singh WR, Devi HS, Kumawat S, et al. Angiogenic and MMPs modulatory effects of icariin improved cutaneous wound healing in rats. Eur J Pharmacol. 2019;858:172466.
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| Files | ||
| Issue | Vol 20 No 1 (2026): Articles In Press | |
| Section | Review Article(s) | |
| Keywords | ||
| Hepatocellular carcinoma; Cancer; Epigenetics; miR-21 | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Alaee M, Moulaee M, Taebi K, Haghi A, Hormozi M, Azad M. The Role of miRNA-21 in the Metastasis of Hepatocellular Carcinoma as a Therapeutic Target. Int J Hematol Oncol Stem Cell Res. 2026;20(1).
