Abstract
Simple SummaryHepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC.Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
Highlights
Liver cancer is the sixth most frequent malignancy and the fourth leading cause of cancer-related deaths worldwide [1]
The risk factors of hepatocarcinogenesis include various liver diseases, such as infections caused by hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholic liver disease (ALD), nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD) [3,4,5]
Each miRNA negatively regulates target genes by binding to the 3 untranslated region (UTR) of mRNAs. These complexes are involved in RNA-mediated interference, and in vertebrates, mRNA transcripts are usually not cleaved by a miRNA-associated RNA-induced silencing complex (RISC) but rather undergo translational repression and degradation via deadenylation [10]
Summary
Liver cancer is the sixth most frequent malignancy and the fourth leading cause of cancer-related deaths worldwide [1]. Double-stranded pre-miRNAs undergo rapid unwinding, when loaded onto Argonaute (AGO), and only one strand, which serves as a guide to target mRNAs, remains bound [21] These RISCs with the AGO protein modulate mRNA degradation and translational inhibition [21]. Reduced SIRT1 levels in the liver of patients with NAFLD can be recovered by the inhibition of miR-34a, which results in the improvement of hepatic steatosis via PPARα and the activation of AMP-activated protein kinase (AMPK) [47]. MiR-206 decreases lipid and glucose levels in hepatocytes by modulating lipogenesis and insulin signaling [52], which suggests that miR-206 might be a diagnostic biomarker and therapeutic target for NAFLD and hyperglycemia
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