MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b∼25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.

Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma

“…To date, most of the studies indicate a critical role of several miRNAs (miR-21, miR-29, miR-23, miR-155, miR-221, miR-222, miR-106, miR-93, miR-519) in NASH-associated carcinogenesis [ 32 ]. Strikingly, altered expression of these miRNAs have been found to be involved in major hepatocarcinogenic pathways, including the TGF- β , Wnt/ β -catenin, mitogen-activate protein kinase (MAPK), and phosphatidylinositol 3-kinases (PI3K)/AKT/mTOR that regulate proliferation and energy metabolism in the cell [ 41 ]. Importantly, several of these miRNAs target the main inhibitor of the PI3K/AKT pathway, PTEN protein, and its mutations were found in HCC patients [ 42 ].…”

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…A further important target gene of miR-221 was shown to be the cell-cycle regulator p27(Kip1) [210,211]. Moreover, miR-221 targets are the E2F transcription factor 1 (E2F1), the phosphatase and tensin homolog (PTEN) and the cyclin-dependent kinase inhibitor 1 (CDKN1A), all belonging to critical cancer related pathways in HCC as well as other types of cancer including melanoma [212]. Bae et al showed that a miR-221 mediated suppression of HDAC6 was initiated by the JNK/c-Jun signaling pathway and by NFκBp65 nuclear translocation [213].…”

“…Regulation of Bcl-2, VEGF and MMP-9 by miR-221 can also induce an invasive phenotype which is further mediated by miR-221 suppressing SCD5 and thereby promoting EMT [193]. Additional miR-221 targets are c-Kit, p27Kip1/CDKN1B and CDKN1A whose downregulation in cancer induces cell proliferation [194,195,212]. MiR-210 can also influence EMT and migration via inhibition of TIMP2 [215] and activation of VMP1 [216].…”

Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD)

“…The targets of microRNA can be multiple genes (multiplicity), or multiple microRNAs can target a single gene (cooperativity). In addition, considering their potential in carcinogenesis, microRNAs can be categorized as oncogenes or onco-microRNAs or as tumor suppressor genes [ 64 ]. miRNAs stability has been demonstrated in serum, plasma, saliva and urine.…”