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

Zhikui Liu, Changwei Dou, Bowen Yao, Meng Xu, Linglong Ding, Yufeng Wang, Yuli Jia, Qing Li, Hongyong Zhang, Kangsheng Tu _, Tao Song and Qingguang Liu

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Oncotarget. 2016; 7:36909-36923. https://doi.org/10.18632/oncotarget.9377

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Abstract

Zhikui Liu1,*, Changwei Dou1,*, Bowen Yao1, Meng Xu1, Linglong Ding1, Yufeng Wang1, Yuli Jia1, Qing Li1, Hongyong Zhang1, Kangsheng Tu1, Tao Song1, Qingguang Liu1

1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

*These authors contributed equally to this work

Correspondence to:

Kangsheng Tu, email: [email protected]

Tao Song, email: [email protected]

Qingguang Liu, email: [email protected]

Keywords: miR-129-2, methylation, high mobility group box 1, invasion, hepatocellular carcinoma

Received: November 22, 2015     Accepted: April 16, 2016     Published: May 15, 2016

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.


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