Prevention and Treatment of Hepatocellular Carcinoma Using miRNAs

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


Introduction
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death around the world. 1-4 Nonviral (alcohol consumption and non-alcoholic fatty liver) 5-7 and viral (hepatitis B/C virus) risk factors 8, 9 enhance the risk of HCC. [10][11][12][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][21][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][26][27] Targeting these signaling pathways may promote the treatment of the disease. [28][29][30] Recent studies have established new approaches for the prevention and treatment of HCC using miRNA technology. [31][32][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 microRNAbinding 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 promoters 42 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 ∼60to 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][50][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 metastasis 54,55 (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).
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.