miR-370 regulates ISG15 expression and influences IFN- [Formula: see text] sensitivity in hepatocellular carcinoma cells

BACKGROUND: Interferon- [Formula: see text] (IFN- [Formula: see text]) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN- [Formula: see text]. METHODS: We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN- [Formula: see text] 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- [Formula: see text] , 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- [Formula: see text]-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 ([Formula: see text] 0.05). The overexpression of miR-370 in IFN- [Formula: see text]-treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN- [Formula: see text] compared with the control tumors. CONCLUSIONS: Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN- [Formula: see text] sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.