Table Info

Table 1.

Role of miRNAs and their target proteins in HCC

S.No	miRNAs	Target proteins	Target pathway	Cellular function in HCC	HCC severity	Reference(s)
1	miR-758-3p	↓ MDM2 ↑ p53, AKT, and PRAS40	mTOR pathway	Inhibits cell propagation, migration and incursion	Reduced HCC progression	[50]
2	miR-142	↓ TGF-β	mTOR pathway	Cell metabolism, propagation, EMT and neo-angiogenesis	Promotes HCC progression and angiogenesis process	[51]
3	miR-199b-5p	↑ N-cadherin ↓ TGF-β1	mTOR pathway	Inhibitory possessions on EMT	Reduced HCC progression	[52]
4	miR-187, miR-497, miR-99a, and miR-592	↑ IGF-1R	mTOR pathway	Cell propagation, migration and incursion	Promotes HCC progression	[53–55]
5	miR-10a, miR-106b, miR-99a, miR-148a, miR-125b, miR-30e, miR-199a, miR-199a3p, miR-24, miR-122, and miR-215	↓ β-catenin and c-myc ↑ APC	Wnt pathway	Inhibits cell propagation	Reduced HCC progression	[58]
6	miR-18a	↓ KLF4, a negative regulator of β-catenin expression	Wnt pathway	Propagation and migration of human HCC	Promotes HCC progression	[59]
7	miR-195	↑ AEG-1	Wnt pathway	Cell propagation, metastasis, angiogenesis and chemoresistance	Promotes HCC progression, angiogenesis and drug resistance	[60]
8	miR-320a	↓ β-catenin, c-myc, cyclin D1, and DKK-1	Wnt pathway	Inhibition of HCC cell propagation and incursion through c-myc suppression	Inhibits HCC progression	[61]
9	miR-98-5p	↓ IGF2BP1	Wnt pathway	Cell propagation	Promotes HCC progression	[62]
10	miR-214-3p	↑ PIM-1	JAK-STAT pathway	Cell propagation	Promotes HCC progression	[65]
11	miR-30e	↓ JAK1	JAK-STAT pathway	Inhibition of cell migration, propagation proliferation and incursion of HCC cells	Inhibits HCC progression	[66]
12	miR-340	↓ JAK-1	JAK-STAT pathway	Inhibits the cell migration, propagation of HCC	Inhibits HCC progression	[67]
13	miR-140-5p and miR-200	↑ Pin-1	JAK-STAT pathway	HCC cell growth and migration	Promotes HCC progression	[69]
14	miR-21	↓ PTEN	PDK1/AKT pathway	Promotes cell migration and incursion of HCC by targeting KLF5	Promotes HCC progression	[70]
15	miR-221	↑ CDKN1B/p27 and CDKN1C/p57	Apoptosis pathway	Promotes cell propagation	Promotes HCC progression	[71]

MDM2: mouse double minute 2; PRAS40: proline-rich Akt substrate 40 kDa; APC: adenomatous polyposis coli; KLF4: Kruppel-like factor 4; AEG-1: astrocyte elevated gene-1; DKK-1: Dickkopf-1; IGF2BP1: insulin-like growth factor 2 mRNA-binding protein 1; PIM-1: proviral integration site for Moloney murine leukemia virus 1; JAK: Janus kinase; Pin-1: peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; CDKN1B: cyclin-dependent kinase inhibitor 1B; ↑: resembles upregulation; ↓: resembles downregulation

Declarations

Author contributions

SBS: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. BV: Conceptualization, Investigation, Validation, Writing—original draft, Writing—review & editing, Supervision. Both authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the Indian Council of Medical Research (ICMR) extramural research grant [5/13/83/2020/NCD/III]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. Erratum in: Nat Rev Dis Primers. 2024;10:10. [DOI] [PubMed] [PMC]

Chu YJ, Yang HI, Wu HC, Lee MH, Liu J, Wang LY, et al. Aflatoxin B₁ exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption. Eur J Cancer. 2018;94:37–46. [DOI] [PubMed] [PMC]

Ferrante ND, Pillai A, Singal AG. Update on the diagnosis and treatment of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2020;16:506–16. [DOI] [PubMed]

Sas Z, Cendrowicz E, Weinhäuser I, Rygiel TP. Tumor microenvironment of hepatocellular carcinoma: challenges and opportunities for new treatment options. Int J Mol Sci. 2022;23:3778. [DOI] [PubMed] [PMC]

Wainwright EN, Scaffidi P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer. 2017;3:372–86. [DOI] [PubMed] [PMC]

Braghini MR, Lo Re O, Romito I, Fernandez-Barrena MG, Barbaro B, Pomella S, et al. Epigenetic remodelling in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41:107. [DOI] [PubMed] [PMC]

Diamond JM. Twenty-first Bowditch lecture. The epithelial junction: bridge, gate, and fence. Physiologist. 1977;20:10–8. [PubMed]

van Meer G, Simons K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J. 1986;5:1455–64. [DOI] [PubMed] [PMC]

Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular biology of the cell. 4th ed. New York: Garland Science; 2002.

10.

Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17:564–80. [DOI] [PubMed]

11.

Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut. 2019;68:547–61. [DOI] [PubMed] [PMC]

12.

Hagen SJ. Non-canonical functions of claudin proteins: beyond the regulation of cell-cell adhesions. Tissue Barriers. 2017;5:e1327839. [DOI] [PubMed] [PMC]

13.

Xiao Y, Lian H, Zhong XS, Krishnachaitanya SS, Cong Y, Dashwood RH, et al. Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin-7. Front Immunol. 2022;13:1020902. [DOI] [PubMed] [PMC]

14.

Marconi GD, Fonticoli L, Rajan TS, Pierdomenico SD, Trubiani O, Pizzicannella J, et al. Epithelial-mesenchymal transition (EMT): the type-2 EMT in wound healing, tissue regeneration and organ fibrosis. Cells. 2021;10:1587. [DOI] [PubMed] [PMC]

15.

Ram AK, Vairappan B, Srinivas BH. Nimbolide attenuates gut dysbiosis and prevents bacterial translocation by improving intestinal barrier integrity and ameliorating inflammation in hepatocellular carcinoma. Phytother Res. 2022;36:2143–60. [DOI] [PubMed]

16.

Ram AK, Vairappan B, Srinivas BH. Nimbolide inhibits tumor growth by restoring hepatic tight junction protein expression and reduced inflammation in an experimental hepatocarcinogenesis. World J Gastroenterol. 2020;26:7131–52. [DOI] [PubMed] [PMC]

17.

Bouchagier KA, Assimakopoulos SF, Karavias DD, Maroulis I, Tzelepi V, Kalofonos H, et al. Expression of claudins-1, -4, -5, -7 and occludin in hepatocellular carcinoma and their relation with classic clinicopathological features and patients’ survival. In Vivo. 2014;28:315–26. [PubMed]

18.

Huang GW, Ding X, Chen SL, Zeng L. Expression of claudin 10 protein in hepatocellular carcinoma: impact on survival. J Cancer Res Clin Oncol. 2011;137:1213–8. [DOI] [PubMed]

19.

Li CP, Cai MY, Jiang LJ, Mai SJ, Chen JW, Wang FW, et al. CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma. Carcinogenesis. 2016;37:557–66. [DOI] [PubMed]

20.

Jiang L, Yang YD, Fu L, Xu W, Liu D, Liang Q, et al. CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma. Oncotarget. 2014;5:7663–76. [DOI] [PubMed] [PMC]

21.

Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, et al. Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene. 2017;36:1167–8. [DOI] [PubMed]

22.

Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FHT, et al. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol. 2015;33:549–54. [DOI] [PubMed] [PMC]

23.

Ram AK, Pottakat B, Vairappan B. Increased systemic zonula occludens 1 associated with inflammation and independent biomarker in patients with hepatocellular carcinoma. BMC Cancer. 2018;18:572. [DOI] [PubMed] [PMC]

24.

Kaikkonen MU, Lam MT, Glass CK. Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res. 2011;90:430–40. [DOI] [PubMed] [PMC]

25.

Macfarlane LA, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11:537–61.

26.

Ha TY. MicroRNAs in human diseases: from cancer to cardiovascular disease. Immune Netw. 2011;11:135–54.

27.

Gu S, Jin L, Zhang F, Sarnow P, Kay MA. Biological basis for restriction of microRNA targets to the 3’ untranslated region in mammalian mRNAs. Nat Struct Mol Biol. 2009;16:144–50. [DOI] [PubMed] [PMC]

28.

Li M, Marin-Muller C, Bharadwaj U, Chow KH, Yao Q, Chen C. MicroRNAs: control and loss of control in human physiology and disease. World J Surg. 2009;33:667–84. [DOI] [PubMed] [PMC]

29.

Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res. 2016;76:3666–70. [DOI] [PubMed] [PMC]

30.

Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102:13944–9. [DOI] [PubMed] [PMC]

31.

Khan S, Zhang DY, Zhang JY, Hayat MK, Ren J, Nasir S, et al. The key role of microRNAs in initiation and progression of hepatocellular carcinoma. Front Oncol. 2022;12:950374. [DOI] [PubMed] [PMC]

32.

Cao MQ, You AB, Zhu XD, Zhang W, Zhang YY, Zhang SZ, et al. miR-182-5p promotes hepatocellular carcinoma progression by repressing FOXO3a. J Hematol Oncol. 2018;11:12. [DOI] [PubMed] [PMC]

33.

Liu L, Zhang W, Hu Y, Ma L, Xu X. Downregulation of miR-1225-5p is pivotal for proliferation, invasion, and migration of HCC cells through NFκB regulation. J Clin Lab Anal. 2020;34:e23474. [DOI] [PubMed] [PMC]

34.

Song Q, An Q, Niu B, Lu X, Zhang N, Cao X. Role of miR-221/222 in tumor development and the underlying mechanism. J Oncol. 2019;2019:7252013. [DOI] [PubMed] [PMC]

35.

Liao Y, Wang C, Yang Z, Liu W, Yuan Y, Li K, et al. Dysregulated Sp1/miR-130b-3p/HOXA5 axis contributes to tumor angiogenesis and progression of hepatocellular carcinoma. Theranostics. 2020;10:5209–24. [DOI] [PubMed] [PMC]

36.

Carbajo-Pescador S, Ordoñez R, Benet M, Jover R, García-Palomo A, Mauriz JL, et al. Inhibition of VEGF expression through blockade of Hif1α and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells. Br J Cancer. 2013;109:83–91. [DOI] [PubMed] [PMC]

37.

Jing BQ, Ou Y, Zhao L, Xie Q, Zhang YX. Experimental study on the prevention of liver cancer angiogenesis via miR-126. Eur Rev Med Pharmacol Sci. 2017;21:5096–100. [DOI] [PubMed]

38.

Raskov H, Orhan A, Gaggar S, Gögenur I. Cancer-associated fibroblasts and tumor-associated macrophages in cancer and cancer immunotherapy. Front Oncol. 2021;11:668731. [DOI] [PubMed] [PMC]

39.

Arvanitakis K, Koletsa T, Mitroulis I, Germanidis G. Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers (Basel). 2022;14:226. [DOI] [PubMed] [PMC]

40.

Graner MW, Schnell S, Olin MR. Tumor-derived exosomes, microRNAs, and cancer immune suppression. Semin Immunopathol. 2018;40:505–15. [DOI] [PubMed] [PMC]

41.

Ismail N, Wang Y, Dakhlallah D, Moldovan L, Agarwal K, Batte K, et al. Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood. 2013;121:984–95. [DOI] [PubMed] [PMC]

42.

Huang F, Zhao JL, Wang L, Gao CC, Liang SQ, An DJ, et al. miR-148a-3p mediates notch signaling to promote the differentiation and M1 activation of macrophages. Front Immunol. 2017;8:1327. [DOI] [PubMed] [PMC]

43.

Zhou SL, Hu ZQ, Zhou ZJ, Dai Z, Wang Z, Cao Y, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology. 2016;63:1560–75. [DOI] [PubMed]

44.

Yugawa K, Yoshizumi T, Mano Y, Itoh S, Harada N, Ikegami T, et al. Cancer-associated fibroblasts promote hepatocellular carcinoma progression through downregulation of exosomal miR-150-3p. Eur J Surg Oncol. 2021;47:384–93. [DOI] [PubMed]

45.

Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res. 2018;37:324. [DOI] [PubMed] [PMC]

46.

Jiang C, Guo Y, Yu H, Lu S, Meng L. Pleiotropic microRNA-21 in pulmonary remodeling: novel insights for molecular mechanism and present advancements. Allergy Asthma Clin Immunol. 2019;15:33. [DOI] [PubMed] [PMC]

47.

Yoon MS. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients. 2017;9:1176. [DOI] [PubMed] [PMC]

48.

Das A, Reis F, Maejima Y, Cai Z, Ren J. mTOR signaling in cardiometabolic disease, cancer, and aging. Oxid Med Cell Longev. 2017;2017:6018675. [DOI] [PubMed] [PMC]

49.

Ngo MT, Jeng HY, Kuo YC, Diony Nanda J, Brahmadhi A, Ling TY, et al. The role of IGF/IGF-1R signaling in hepatocellular carcinomas: stemness-related properties and drug resistance. Int J Mol Sci. 2021;22:1931. [DOI] [PubMed] [PMC]

50.

Jiang D, Cho WC, Li Z, Xu X, Qu Y, Jiang Z, et al. MiR-758-3p suppresses proliferation, migration and invasion of hepatocellular carcinoma cells via targeting MDM2 and mTOR. Biomed Pharmacother. 2017;96:535–44. [DOI] [PubMed]

51.

Yu Q, Xiang L, Yin L, Liu X, Yang D, Zhou J. Loss-of-function of miR-142 by hypermethylation promotes TGF-β-mediated tumour growth and metastasis in hepatocellular carcinoma. Cell Prolif. 2017;50:e12384. [DOI] [PubMed] [PMC]

52.

Zhou SJ, Liu FY, Zhang AH, Liang HF, Wang Y, Ma R, et al. MicroRNA-199b-5p attenuates TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Br J Cancer. 2017;117:233–44.

53.

Cheng H, Xue J, Yang S, Chen Y, Wang Y, Zhu Y, et al. Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development. Oncotarget. 2017;8:47984–97. [DOI] [PubMed] [PMC]

54.

Wang W, Zhang H, Tang M, Liu L, Zhou Z, Zhang S, et al. MicroRNA-592 targets IGF-1R to suppress cellular proliferation, migration and invasion in hepatocellular carcinoma. Oncol Lett. 2017;13:3522–8. [DOI] [PubMed] [PMC]

55.

Han X, Wang X, Zhao B, Chen G, Sheng Y, Wang W, et al. MicroRNA-187 inhibits tumor growth and metastasis via targeting of IGF-1R in hepatocellular carcinoma. Mol Med Rep. 2017;16:2241–6. [DOI] [PubMed]

56.

Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3. [DOI] [PMC]

57.

Sangkhathat S, Kusafuka T, Miao J, Yoneda A, Nara K, Yamamoto S, et al. In vitro RNA interference against beta-catenin inhibits the proliferation of pediatric hepatic tumors. Int J Oncol. 2006;28:715–22. [PubMed]

58.

Ashmawy AM, Elgeshy KM, Abdel Salam ET, Ghareeb M, Kobaisi MH, Amin HAA, et al. Crosstalk between liver-related microRNAs and Wnt/β-catenin pathway in hepatocellular carcinoma patients. Arab J Gastroenterol. 2017;18:144–50. [DOI] [PubMed]

59.

Wang X, Lu J, Cao J, Ma B, Gao C, Qi F. MicroRNA-18a promotes hepatocellular carcinoma proliferation, migration, and invasion by targeting Bcl2L10. Onco Targets Ther. 2018;11:7919–34. [DOI] [PubMed] [PMC]

60.

Yan JJ, Chang Y, Zhang YN, Lin JS, He XX, Huang HJ. miR-195 inhibits cell proliferation via targeting AEG-1 in hepatocellular carcinoma. Oncol Lett. 2017;13:3118–26. [DOI] [PubMed] [PMC]

61.

Lu C, Liao Z, Cai M, Zhang G. MicroRNA-320a downregulation mediates human liver cancer cell proliferation through the Wnt/β-catenin signaling pathway. Oncol Lett. 2017;13:573–8. [DOI] [PubMed] [PMC]

62.

Jiang T, Li M, Li Q, Guo Z, Sun X, Zhang X, et al. MicroRNA-98-5p inhibits cell proliferation and induces cell apoptosis in hepatocellular carcinoma via targeting IGF2BP1. Oncol Res. 2017;25:1117–27. [DOI] [PubMed] [PMC]

63.

Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113:365–71. [DOI] [PubMed] [PMC]

64.

Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, et al. Pim-1 kinase as cancer drug target: an update. Biomed Rep. 2016;4:140–6. [DOI] [PubMed] [PMC]

65.

Huang PS, Lin YH, Chi HC, Chen PY, Huang YH, Yeh CT, et al. Thyroid hormone inhibits growth of hepatoma cells through induction of miR-214. Sci Rep. 2017;7:14868. [DOI] [PubMed] [PMC]

66.

Mao J, Hu X, Pang P, Zhou B, Li D, Shan H. miR-30e acts as a tumor suppressor in hepatocellular carcinoma partly via JAK1/STAT3 pathway. Oncol Rep. 2017;38:393–401. [DOI] [PubMed]

67.

Yuan J, Ji H, Xiao F, Lin Z, Zhao X, Wang Z, et al. MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1. Biochem Biophys Res Commun. 2017;483:578–84. [DOI] [PubMed]

68.

Cheng CW, Tse E. Targeting PIN1 as a therapeutic approach for hepatocellular carcinoma. Front Cell Dev Biol. 2020;7:369. [DOI] [PubMed] [PMC]

69.

Yan X, Zhu Z, Xu S, Yang LN, Liao XH, Zheng M, et al. MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways. Sci Rep. 2017;7:45915. [DOI] [PubMed] [PMC]

70.

Wang J, Chu Y, Xu M, Zhang X, Zhou Y, Xu M. miR-21 promotes cell migration and invasion of hepatocellular carcinoma by targeting KLF5. Oncol Lett. 2019;17:2221–7. [DOI] [PubMed] [PMC]

71.

Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27:5651–61. [DOI] [PubMed]

72.

Yang J, Liu X, Yuan X, Wang Z. miR-99b promotes metastasis of hepatocellular carcinoma through inhibition of claudin 11 expression and may serve as a prognostic marker. Oncol Rep. 2015;34:1415–23. [DOI] [PubMed]

73.

Gao Y, Luo T, Ouyang X, Zhu C, Zhu J, Qin X. IGF2BP3 and miR191-5p synergistically increase HCC cell invasiveness by altering ZO-1 expression. Oncol Lett. 2020;20:1423–31. [DOI] [PubMed] [PMC]

74.

Wang SC, Lin XL, Li J, Zhang TT, Wang HY, Shi JW, et al. MicroRNA-122 triggers mesenchymal-epithelial transition and suppresses hepatocellular carcinoma cell motility and invasion by targeting RhoA. PLoS One. 2014;9:e101330. [DOI] [PubMed] [PMC]

75.

Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin YF, Yuan Y, et al. Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology. 2018;68:1459–75. [DOI] [PubMed]

76.

Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6. [DOI] [PubMed] [PMC]

77.

Lu Y, Han G, Zhang Y, Zhang L, Li Z, Wang Q, et al. M2 macrophage-secreted exosomes promote metastasis and increase vascular permeability in hepatocellular carcinoma. Cell Commun Signal. 2023;21:299. [DOI] [PubMed] [PMC]