Xinlong Yan 1 , 2 , Dongdong Zhang 3 , 4 , Wei Wu 3 , 4 , 5 , Shuheng Wu 3 , 4 , 5 , Jingfeng Qian 3 , 4 , Yajing Hao 3 , 4 , 5 , Fang Yan 6 , Pingping Zhu 2 , Jiayi Wu 2 , 5 , Guanling Huang 2 , Yinghui Huang 7 , Jianjun Luo 3 , 4 , Xinhui Liu 7 , Benyu Liu 2 , 5 , Xiaomin Chen 3 , 4 , Ying Du 2 , Runsheng Chen 8 , 4 , 5 , Zusen Fan 9 , 5
Dec 01 2017
Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704-16. ©2017 AACR.