Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma

Abstract

Aberrant expression of microRNAs (miRNAs) and its dysfunction have been revealed as crucial modulators of cancer initiation and progression. MiR-129-2 has been reported to play a tumor suppressive role in different human malignancies. Here, we demonstrated that miR-129-2 was significantly decreased in hepatocellular carcinoma (HCC) tissues and cell lines. Furthermore, miR-129-2 was expressed at significant lower levels in aggressive and recurrent tumor tissues. Clinical analysis indicated that miR-129-2 expression was inversely correlated with venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) stage in HCC. Notably, miR-129-2 was an independent prognostic factor for indicating overall survival (OS) and disease-free survival (DFS) of HCC patients. Ectopic expression of miR-129-2 inhibited cell migration and invasion in vitro and in vivo. Furthermore, we confirmed that high mobility group box 1 (HMGB1) was a direct target of miR-129-2, and it abrogated the function of miR-129-2 in HCC. Mechanistic investigations showed that miR-129-2 overexpression inhibited AKT phosphorylation at Ser473 and decreased the expression of matrix metalloproteinase2/9 (MMP2/9). Upregulation of p-AKT abolished the decreased cell migration and invasion induced by miR-129-2 in HCC. Whereas inhibition of Akt phosphorylation significantly decreased HMGB1-enhanced HCC cell migration and invasion. Moreover, we found that miR- 129-2 was downregulated by DNA methylation, and demethylation of miR-129-2 increased miR-129-2 expression in HCC cells and resulted in significant inhibitory effects on cell migration and invasion. In conclusion, miR-129-2 may serve as a prognostic indicator for HCC patients and exerts tumor suppressive role, at least in part, by inhibiting HMGB1.