MiR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.

Abstract

BACKGROUND: Interferon- (IFN-) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-.METHODS: We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN- sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples.RESULTS: The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3’-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN--induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues ( 0.05). The overexpression of miR-370 in IFN--treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN- compared with the control tumors.CONCLUSIONS: Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN- sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.