// Li-Li Liu 1,2,* , Shi-Xun Lu 1,2,* , Min Li 1,2 , Lin-Zi Li 1,2 , Jia Fu 1,2 , Wen Hu 1,2 , Yuan-Zhong Yang 1,2 , Rong-Zhen Luo 1,2 , Chris Zhiyi Zhang 1,2 , Jing-Ping Yun 1,2 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine 2 Department of Pathology, Sun Yat-sen University Cancer Center * These authors contributed equally to this work Correspondence: Chris Zhiyi Zhang, email: // Jing-Ping Yun, email: // Keywords : miR-137; AKT2; FoxD3; metastasis; HCC Received : May 3, 2014 Accepted : June 9, 2014 Published : June 10, 2014 Abstract microRNAs, frequently deregulated in human cancer, have been implicated in the progression of hepatocarcinogenesis. Here, we show that microRNA (miR)-137 is significantly down-regulated in hepatocellular carcinoma (HCC). Its decreased expression is associated with vein invasion, incomplete involucrum, and distant metastasis. Multivariate analysis suggests that miR-137 is an independent indicator for poor survival. We next show that over-expression of miR-137 suppresses cell proliferation, migration and invasion in vitro . Conversely, miR-137 inhibition promotes HCC cell growth. We also identify AKT2 as a key target of miR-137 in this context. Statistical data reveal a reverse correlation of AKT2 and miR-137 expression in HCC patients. Silencing of AKT2 phenotypically copied miR-137-induced phenotypes, whereas re-expression of AKT2 reversed the suppressive effects of miR-137. Further investigations showed that miR-137 exerted its anti-tumour activity via inhibiting the AKT2/mTOR pathway. Moreover, we demonstrate that FoxD3 directly binds to the promoter of miR-137 and activates its transcription. In vivo studies confirm that FoxD3-regulated miR-137 inhibited HCC growth and metastasis via targeting AKT2. Together, our findings indicate that miR-137 is a valuable biomarker for HCC prognosis and the FoxD3/miR-137/AKT2 regulatory network plays an important role in HCC progression.
