title: FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2.
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.
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center. These authors contributed equally to this work.
authors: Li-Li
authors: LL
authors: Liu
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center. These authors contributed equally to this work.
authors: Shi-Xun
authors: SX
authors: Lu
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Min
authors: M
authors: Li
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Lin-Zi
authors: LZ
authors: Li
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Jia
authors: J
authors: Fu
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Wen
authors: W
authors: Hu
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Yuan-Zhong
authors: YZ
authors: Yang
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Rong-Zhen
authors: RZ
authors: Luo
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Chris Zhiyi
authors: CZ
authors: Zhang
authors: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine. Department of Pathology, Sun Yat-sen University Cancer Center.
authors: Jing-Ping
authors: JP
authors: Yun
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020413:3' Untranslated Regions; C503514:FOXD3 protein, human; D051858:Forkhead Transcription Factors; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt