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Arch Iran Med. 25(2):133-138. doi: 10.34172/aim.2022.23

Mini Review

Prevention and Treatment of Hepatocellular Carcinoma Using miRNAs

Zahra Farzaneh 1, Maryam Farzaneh 2, 3, * ORCID logo

Author information:
1Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
2Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

*Corresponding Author: Maryam Farzaneh, PhD; Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Email: Maryamfarzaneh2013@yahoo.com

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of death due to cancer. Liver transplantation, surgical liver resection, chemotherapy, and radiotherapy are the main options for the treatment of HCC. However, these methods are unable to limit the growth, survival, and metastasis of HCC cells. Several signaling pathways control propagation, metastasis, and recurrence of HCC. Recent studies have established new approaches for the prevention and treatment of HCC using miRNA technology. MicroRNAs are a class of non-coding RNAs with an average of 22 nucleotides that play critical roles in controlling gene expression in a variety of biological processes. miRNAs can induce or suppress HCC proliferation, migration, metastasis, and tumorigenesis. The anti-cancer effects of molecular agents can be evaluated directly in animal models or indirectly through the injection of HCC cell lines treated with anti-cancer agents. Targeting cancer-specific signaling pathways with miRNAs can be novel therapeutic strategies against HCC. This study provides the latest findings on using miRNAs in the control of HCC in both in vitro and in vivo models.

Keywords: Cancer, Hepatocellular carcinoma, miRNA, Signaling pathways

Copyright and License Information

© 2022 The Author(s).
This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cite this article as: Farzaneh Z, Farzaneh M. Prevention and treatment of hepatocellular carcinoma using miRNAs. Arch Iran Med. 2022;25(2):133-138. doi: 10.34172/aim.2022.23

Introduction

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death around the world.1-4 Non-viral (alcohol consumption and non-alcoholic fatty liver)5-7 and viral (hepatitis B/C virus) risk factors8,9 enhance the risk of HCC.10-13 There are three main options, including liver transplantation,14-16 surgical liver resection,17-19 and non-surgical methods (chemotherapy and radiotherapy) for the treatment of HCC.20-22 However, these approaches are unable to limit the progression and metastasis of HCC cells and cause side effects on the surrounding healthy cells.23,24 Several signaling pathways, including Wnt, Notch, EGF, SHH, hippo, and BMPs are associated with cell-division, metastasis, epithelial to mesenchymal transition (EMT), migration, and tumorigenesis of HCC.25-27 Targeting these signaling pathways may promote the treatment of the disease.28-30 Recent studies have established new approaches for the prevention and treatment of HCC using miRNA technology.31-33 microRNAs are a branch of RNA interference (RNAi) technology that contain about 20 nucleotides and target the specific mRNA in the cells.34,35 Evidence from miRNA expression profiles shows that some miRNAs are upregulated in HCC (oncomiR) and enhance the acquisition of metastatic potential.36,37 miRNAs can inhibit the expression of specific proteins (ligand or secondary messenger) in tumor-promoting signaling pathways and enhance HCC treatment efficacy.38,39 Molecularly targeted therapies using miRNAs with a high degree of specificity may be a suitable strategy in cancer treatment.31,40,41 This study provides the latest findings on using miRNAs in the control of HCC in both in vitro and in vivo models.

The Canonical miRNA Biogenesis

MicroRNAs are a class of non-coding RNAs with an average of 22 nucleotides that play an important role in controlling gene expression.42 miRNAs by microRNA-binding sites in the 3′ UTR of the target mRNAs trigger mRNA degradation to control the rate of translation.43 miRNAs can bind with the 5′ UTR, coding sequences, and gene promoters42 to regulate the expression of target genes or suppress translation by one of two distinct mechanisms.44 Pri-miRNAs or primary miRNAs are produced by the RNase II or III (poll III) in the nucleus.45,46 Subsequently, pri-miRNA with the Drosha/DGCR8 holoenzyme undergoes nuclear cleavage to produce a hairpin structured precursor or the precursor miRNA (pre-miRNA) with ∼60- to 70-nt.47 Exportin-5 (Exp5) and Ran-GTP can transport pre-miRNAs to the cytoplasm.48 Dicer is an RNase III endonuclease that combined with the transactivating response RNA-binding protein (TRBP) cleaves pre-miRNA hairpin to form a mature microRNA duplex (∼22-nt).49-51 Finally, miRNA binds with the AGO protein (RNA-induced silencing complex (RISC)) to target messenger RNA (mRNA) and stimulate mRNA cleavage, degradation, and translation repression.52,53 (Figure 1).

Targeting Signaling Pathways in HCC with miRNAs

Several previous studies have provided evidence that miRNA can suppress HCC metastasis54,55 (Table 1). miRNAs have been shown to control several signaling pathways, including Wnt, Notch, FGF, SHH, and hippo, and suppress the tumorigenesis of HCC (Figure 1).


Table 1. Effects of miRNA on Signaling Pathways Related to HCC
Pathway miRNA Target HCC cell line Animal model Result Ref.
TGF-B miR-200 Ligand MHCC-97 H, SMMC 7721, HepG2, Huh7 - Inhibit HCC proliferation, EMT, and invasion 56
miR-663 Ligand SK-Hep1, Huh7 and other HCC line - Inhibit the tumor growth and invasion 57
miR-34 Ligand Huh7, HepG2, Hep3B - Decrease the HCC proliferation 58
miR-133 SMMC7721, Huh7 1 × 107 SMMC7721 d subcutaneously to limb of nude mice Decrease proliferation, migration, increase apoptosis, decrease tumor growth 59
Wnt miR-298 B-catenin MHCC-97 H, HCCLM3 MHCC-97H subcutaneously to flank of nude mice Decrease the HCC proliferation and metastasis 60
miR-504 FZD receptor Huh7, HepG2 - Decrease the HCC proliferation and metastasis 60
miR-122 Pathway SMMC7721, Bel-7402 5×106 cells subcutaneously to flank of nude mice Decrease the HCC proliferation, survival and tumor weight 61
miR-148b Wnt1 HepG2 5 × 106 HepG2 subcutaneously to flank of nude mice Induce apoptosis and cell cycle arrest, inhibit tumor growth 62
miR- 3194-3p BCL9 MHCC-97H, Hep3B 1 × 106 MHCC-97H or Hep3B to tail veins Inhibit migration, invasion, and metastasis 63
Shh miR-138 Smo receptor HepG2 - Decrease colony formation and invasion, increase apoptosis 64
miR-338-3p Smo receptor MHCC-97H 1×107 MHCC-97H to flank of nude mice then cut and transplant to left liver Inhibit the EMT 65
Notch miR-3163 NICD MHCC97-H, LM-3 MHCC97-H subcutaneous or intraportal of nude mice Decrease the tumor growth 66
miR-206 NICD HepG2 - Cell cycle arrest, apoptosis, and inhibit the EMT 67
EGF miR-874 ERK SK-Hep1 overexpressed miR-874 SK-hep-1 to BALB/c nude mice Inhibit proliferation and metastasis, decrease the tumor size 68
HGF miR-181a-5p c-met SNU, Mahlavu - Inhibit proliferation and metastasis 69
VEGF miR-195 VEGF/FGF BEL-7402 - Inhibit migration and invasion 70
miR-126 EGF/VEGF HCCLM3, SMMC-7721, MHCC-97H subcutaneously to flank of SCID mouse Inhibit proliferation and tumor growth 71
Stat3 miR-345 Jak HCCLM3, HepG2 6×106 HCCLM3 cells intravenously into nude mice Inhibit the EMT and metastasis 72
miR-30e Jak HepG2, Huh7 - Inhibit the proliferation, migration, and invasion of HCC 73
YAP/TAZ miR-9-3p TAZ Huh1, HLF - Inhibit proliferation 74
miR186 YAP HepG2, Hep3B, SNU398 - Inhibit the migration and proliferation 75
HIF-1α miR-592 HIF-1α SK-hep1, SMMC-7721 1.5 × 106 SK-Hep-1 subcutaneously into flank of SCID mice Inhibit proliferation tumor growth, and glycolysis 76
Cell cycle miR-144 Cyclin B1 HepG2, SMMC-7721 5 × 106 SMMC-7721 subcutaneously to flanks of nude mice Decrease proliferation, migration, survival, and the tumor size 77
miR-214-3p Serin, theronin kinase HepG2, Huh7 - Decrease proliferation, increase the apoptosis 56
miR-300 B-Catenin HepG2, Huh7 - Decrease proliferation 78
Apoptosis miR-383 Stat3 HepG2, Huh7 DEN Increase the apoptosis, decrease proliferation 79
miR-644a Heat shock factor 1 HepG2, SMMC-7721 2 × 107 SMMC-7221 subcutaneously to nude mice Increase the apoptosis, decrease proliferation
inhibit tumor growth		 80
miR-377 Bcl2 HepG2 - Inhibit proliferation and apoptosis 81
Autophagy miR-423-5p ATG7 Huh7 - Autophagy and cell cycle arrest 82
miR100 mTOR HepG2 5×106 HepG2 subcutaneously to flank of BALB/c mice Autophagy and apoptosis 81
ROS miR-125b-5p TXNRD Huh7, SK-hep1 - Decrease proliferation and migration 81
miR-124 SIRT1 Huh7, HepG2 5×106 HepG2 subcutaneously to armpit of nude mice Increase the apoptosis in combination with Cisplatin 83
aim-25-133-g001
Figure 1.

miRNA Biogenesis and Anti-oncogenic Functions on Signaling Pathways Related to Hepatocellular Carcinoma.


It has been shown that overexpression of miR-34, miR-200, miR-133, and miR-663a inhibits the activation of the TGF-β ligand.56,57,59 miR-122 and miR-3194-3p have been found to suppress the Wnt/β-catenin pathway in HCC.61,63 Ectopic overexpression of miR-504 in HCC cells leads to blocking the FZD, while the overexpression of miR-298 and miR-148-b inhibits the activation of β-catenin.60,62 Overexpression of miR-13864 and miR-338-3p was shown to suppress Smo in the SHH pathway.65 Interestingly, SHH inhibitors accompanied by radiotherapy enhanced the radiosensitivity of HCC.84 miR-3163 and miR-206 have been reported to suppress the notch 1 intracellular domain (NICD) transcriptional activation in the Notch pathway.66,67 It has been confirmed that miR-874 blocks the EGF/ERK pathway in HCC.68 miR-181a-5p as a selective c-MET inhibitor in the HGF pathway decreases HCC proliferation, migration, and tumor growth.69,85-87 miR-195 inhibits angiogenesis by targeting VEGF and FGF,70 while miR-126 decreases the expression of VEGF and EGF.71 miR-30e and miR-345 are able to target the Jak/Stat3 pathway.72,73 miR-186 and miR-9-3p as tumor suppressors repress YAP75 and TAZ74 in the hippo pathway. Overexpression of miR-592 leads to disruption of hypoxia-inducible factor-1α (HIF-1α), suppression of glycolysis and lactate production, and reduction of G6PD mRNA levels in HCC.76

Anti-proliferative miRNA are significantly downregulated in HCC cell lines.78 Overexpression of miR-214-3p was reported that reduced HCC progression, by binding to the 3′-UTR of maternal embryonic leucine zipper kinase expression.88 miR-144 and miR-300 by targeting cyclin B and β-catenin, respectively, couldpromote cell cycle arrest in HCC.77,78,9 miR-383 by targeting IL-17 can suppress the Stat3 function, miR-644a inhibits heat shock factor 1 (an anti-apoptotic transcription factor), and miR-377 represses Bcl-2, thereby increasing apoptosis and decreasing cellular proliferation in HCC.79-81 Several studies have shown that miR100 and miR-423-5p induce autophagy.82,90 miR-124 interacts with sirtuin 1 (SIRT1) protein to enhance the cytotoxic effects of cisplatin in the CSC subpopulation.83

Taken together, targeting cancer-specific signaling pathways using miRNAs may be novel therapeutic strategies against HCC.

In conclusion, several important signaling pathways are misregulated in HCC compared to the normal hepatocytes.91,92 These pathways can trigger EMT, metastasis, migration, and tumorigenesis. Hence, suppression of the critical pathways with miRNAs causes cell cycle arrest, apoptosis, inhibits the tumorigenesis of HCC, and facilitates the sensitivity of HCC cells to drugs. Therefore, miRNAs may be a valuable approach to HCC treatment.93

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Statement

Not applicable.

Conflict of Interest Disclosures

The authors declare no conflict of interest.

Funding

None declared.

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Article History

Submitted: 17 Jun 2021
Accepted: 18 Jul 2021
First published online: 01 Feb 2022

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