Oncotarget

Research Papers:

miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

Yan-Yan Jia _, Jin-Yi Zhao, Bing-Ling Li, Kai Gao, Ying Song, Mei-You Liu, Xiao-Juan Yang, Yan Xue, Ai-Dong Wen and Lei Shi

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Oncotarget. 2016; 7:35257-35269. https://doi.org/10.18632/oncotarget.9135

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Abstract

Yan-Yan Jia1,2,*, Jin-Yi Zhao2,*, Bing-Ling Li1,*, Kai Gao2,*, Ying Song2, Mei-You Liu2, Xiao-Juan Yang2, Yan Xue3, Ai-Dong Wen2, Lei Shi1

1Department of Pharmacy, General Hospital of Guangzhou Military Command of People’s Liberation Army, Guangzhou, Guangdong, P. R. China

2Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P. R. China

3Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Lei Shi, email: xjyypharmacy@126.com

Ai-Dong Wen, email: adwen-2004@hotmail.com

Yan Xue, email: 25961754@qq.com

Keywords: hepatocellular carcinoma, miR-592, hypoxia inducible factor-1α, glycolysis, WSB1

Received: December 17, 2015    Accepted: April 02, 2016    Published: May 2, 2016

ABSTRACT

Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3’-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.


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