Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. It has been demonstrated that aberrant expression of miRNAs plays an important role in HCC development. Here, we observed decreased miR-125b expression status in tumor samples from HCC patients, and the five years survival rate of HCC patients with low miR-125b expression is poor. By using bioinformatics prediction tools combining with luciferase reporter assay, we identified that miR-125b can suppress the expression of SIRT6 by directly targeting the seed-matching region of its 3'UTR. Based on the analysis via TCGA and clinical samples data, the expression of SIRT6 showed negatively correlated with the expression of mir-125b. After knocking-out the expression of SIRT6 through CRISPR/Cas9, HCC cells showed the decreased cell viability and invasiveness, which had the similar function upon the overexpression of the miR-125b. The function induced by overexpression of miR-125b can be rescued by the restoration of SIRT6. Further experiments demonstrated that the HCC cells showed the significant cellular senescence and apoptosis upon overexpression of miR-125b or knockout SIRT6, which is in accordance with the compromised cell malignancy. Thus, we conclude that, by targeting SIRT6, miR-125b can function as a tumor suppressor to induce the cellular senescence and apoptosis in hepatocellular carcinogenesis and could provide a novel insight for HCC treatment.
Keywords: CRISPR/Cas9; SIRT6; hepatocellular carcinoma; microRNA; senescence.