HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1

Abstract

The hepatitis C virus (HCV) core protein is critical in the development of hepatocellular carcinoma (HCC). Investigations on HCC have previously focused on microRNAs, a class of small non‑coding RNAs, which are crucial in cancer development and progression. The present study aimed to investigate whether microRNA (miR)‑196a is aberrantly regulated by the HCV core protein, and whether miR‑196a is involved in the regulation of the aberrant proliferation of HCV‑HCC cells. In the study, miRNA expression was detected by quantitative polymerase chain reaction analysis. An Ad‑HCV core adenovirus was constructed and cell proliferation was measured using a Cell Counting Kit-8 assay and a cell cycle assay following infection. The results of the present study demonstrated that the HCV core protein increased the expression of miR‑196a, and that overexpression of miR‑196a in the HepG2 and Huh‑7 HCC cell lines promoted cell proliferation by inducing the G1‑S transition. Furthermore, the present study demonstrated that forkhead box O1 (FOXO1) was directly regulated by miR‑196a, and was essential in mediating the biological effects of miR‑196a in HCC. The overexpression of FOXO1 markedly reversed the effect of miR‑196a in HCC cell proliferation. Taken together, the data obtained in the present study provided compelling evidence that elevated expression levels of miR‑196a by the HCV core protein can function as an onco‑microRNA during HCV‑induced cell proliferation by downregulating the expression of FOXO1, indicating a potential novel therapeutic target for HCV-related HCC.

Viral hepatitis and liver cancer

“…HCV infection regulates expression of several miRs, including miR-146a-5p [ 119 ], miR-196a [ 120 ] and miR-135a-5p [ 27 ], that regulate metabolic pathways and hepatocarcinogenesis. Expression levels of the liver-specific miR-122 are inversely associated with HCC of non-viral origin and yet are conserved in HCV–HCC [ 121 ].…”

MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

“…**P < 0.01, ***P < 0.001 migration, and invasion but induced cell apoptosis by targeting forkhead transcription factor O1 (FOXO1) in HCC 22 . Moreover, miR-196a was reported to contribute to cell proliferation through regulating cell cycle via targeting FOXO1 in HCC 23 . As for miR-196b, it was shown to predict poor prognosis and increase cell migration as well as invasion in HCC by regulating FOXP2 24 .…”

“…Functional miRNAs are known to regulate targets expressions by binding their 3′-UTR sequences 26 . This research explored multiple targets of miR-196a and miR-196b and previous studies have validated the interaction between them and FOXO1, FOXP2, or lysosomeassociated protein transmembrane-4β (LAPTM4B) in HCC [22][23][24]27 . SOCS proteins mediate inflammation and apoptosis via regulating immune homeostasis in human cancers.…”

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

“…Expression of MIR196A1 miRNA has been correlated with expression of the endometrial cancer candidate target gene KLF5 in breast tumors, and has been associated with poor outcome in breast and ovarian cancer patients [38,39]. MIR196A1 miRNA inhibits a range of cancer cell phenotypes including apoptosis, proliferation, migration and invasion [37,[40][41][42]. Consistent with these findings, MIR196A1 miRNA levels are lower in endometrial tumors compared with healthy endometrial tissue [42].…”