Research Papers:

Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma

Jiangbo Zhang _, Jin Cheng, Zhenzhen Zeng, Yongfeng Wang, Xiaojun Li, Qing Xie, Junqiao Jia, Ying Yan, Zhengyang Guo, Jian Gao, Mingjie Yao, Xiangmei Chen and Fengmin Lu

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Oncotarget. 2015; 6:42040-42052. https://doi.org/10.18632/oncotarget.5969

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Jiangbo Zhang1,2,*, Jin Cheng1,3,*, Zhenzhen Zeng1,*, Yongfeng Wang1, Xiaojun Li1, Qing Xie4, Junqiao Jia1, Ying Yan1, Zhengyang Guo1, Jian Gao1, Mingjie Yao1, Xiangmei Chen1, Fengmin Lu1

1Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China

3Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, Beijing 100191, China

4Department of Clinical Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China

*These authors have contributed equally to this work

Correspondence to:

Fengmin Lu, e-mail: [email protected]

Xiangmei Chen, e-mail: [email protected]

Keywords: microRNA-9, hepatocellular carcinoma, hypermethylation, IGF2BP1, AKT&ERK

Received: May 03, 2015     Accepted: October 09, 2015     Published: October 19, 2015


MicroRNA-9 (miR-9) dysregulation is implicated in a variety of human malignancies including hepatocellular carcinoma (HCC), but its role remains contradictory. In this study, we explored the expression and methylation status of miR-9 in HCC samples, as well as the tumor-related functions of miR-9 in vitro. Bioinformatics analysis, array-based RNA expression profile, and literature retrieval were used to identify miR-9 targets in HCC. The potential downstream candidates were then validated by luciferase reporter assay, real-time quantitative PCR, and western blot or enzyme linked immunosorbent assay (ELISA). The expression status and clinicopathologic significances of miR-9 target genes in clinical samples were further explored. The results showed that miR-9 was frequently downregulated in primary HCC. Its silencing was largely contributed by a high frequency (42.5%) of mir-9-1 hypermethylation, which was correlated with bigger tumor size (P = 0.0234). In vitro functional studies revealed that miR-9 restoration retarded HCC cell proliferation and migration. IL-6, AP3B1, TC10, ONECUT2, IGF2BP1, MYO1D, and ANXA2 were confirmed to be miR-9 targets in HCC. Among them, ONECUT2, IGF2BP1, and ANXA2 were confirmed to be aberrantly upregulated in HCC. Moreover, upregulation of ONECUT2, IGF2BP1, and IL-6 were significantly associated with poor post-surgery prognosis (P = 0.0458, P = 0.0037 and P = 0.0461, respectively). Mechanically, miR-9 plays a tumor suppressive role partially through a functional miR-9/IGF2BP1/AKT&ERK axis. Our study suggests that miR-9 functions as a tumor suppressor in HCC progression by inhibiting a series of target genes, including the newly validated miR-9/IGF2BP1/AKT&ERK axis, thus providing potential therapeutic targets and novel prognostic biomarkers for HCC patients.

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