Jia Yan-Yan, Zhao Jin-Yi, Li Bing-Ling, Gao Kai, Song Ying, Liu Mei-You, Yang Xiao-Juan, Xue Yan, Wen Ai-Dong, Shi Lei
Department of Pharmacy, General Hospital of Guangzhou Military Command of People's Liberation Army, Guangzhou, Guangdong, P. R. China.
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
Oncotarget. 2016 Jun 7;7(23):35257-69. doi: 10.18632/oncotarget.9135.
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.
肝细胞癌（HCC）细胞为了高效增殖，会迅速将其能量来源从氧化磷酸化转变为糖酵解代谢。然而，负责这种转变的分子机制仍不清楚。在本研究中，我们发现miR-592在人类HCC组织和细胞系中经常下调，其下调与HCC患者的侵袭性临床病理特征和不良预后密切相关。miR-592的过表达在体外抑制了HCC细胞的有氧糖酵解和增殖。相反，在皮下注射和原位肝肿瘤植入模型中，敲低miR-592均促进了体内HCC的生长。从机制上讲，人类HCC中miR-592的下调与含WD重复序列和SOCS盒蛋白1（WSB1）的上调相关。我们进一步表明，miR-592直接与WSB1基因的3'-UTR结合，从而破坏缺氧诱导因子-1α（HIF-1α）蛋白的稳定性。反过来，HCC细胞中WSB1的过表达挽救了由miR-592诱导的HIF-1α表达降低、葡萄糖摄取减少和HCC生长受抑制的情况。总体而言，我们的临床数据和功能研究表明，miR-592是一种新的、强大的Warburg效应抑制剂，也是HCC治疗中一个有前景的治疗靶点。
