FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2
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Li-Li Liu1,2,*, Shi-Xun Lu1,2,*, Min Li1,2, Lin-Zi Li1,2, Jia Fu1,2, Wen Hu1,2, Yuan-Zhong Yang1,2, Rong-Zhen Luo1,2, Chris Zhiyi Zhang1,2, Jing-Ping Yun1,2
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
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
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.
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