Genome-wide screening reveals that miR-195 targets the TNF-α/NF-κB pathway by down-regulating IκB kinase alpha and TAB3 in hepatocellular carcinoma

Authors

  • Jie Ding,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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    • These authors contributed equally to this work.

  • Shenglin Huang,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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    • These authors contributed equally to this work.

  • Ying Wang,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Qi Tian,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Ruopeng Zha,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Haibing Shi,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Qifeng Wang,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Chao Ge,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Taoyang Chen,

    1. Qi Dong Liver Cancer Institute, Qi Dong, China
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  • Yingjun Zhao,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Linhui Liang,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Jinjun Li,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Xianghuo He

    Corresponding author
    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • Address reprint requests to: Xianghuo He, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No.25/Ln.2200, Xie Tu Road, Shanghai 200032, China. E-mail: xhhe@shsci.org; fax: +86-21-64436539.

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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the National Natural Science Foundation of China (91029728, 81101481, 81125016), Shanghai Rising-Star and Young Medical Talent Training Program (11QA1406100, XYQ2011048), Shanghai Municipal Education Commission, and Shanghai Municipal Health Bureau (11SG18, 20114Y159).

Abstract

Nuclear factor kappa B (NF-κB) is an important factor linking inflammation and tumorigenesis. In this study we experimentally demonstrated through a high-throughput luciferase reporter screen that NF-κB signaling can be directly targeted by nearly 29 microRNAs (miRNAs). Many of these miRNAs can directly target NF-κB signaling nodes by binding to their 3′ untranslated region (UTR). miR-195, a member of the miR-15 family, is frequently down-regulated in gastrointestinal cancers, especially in hepatocellular carcinoma (HCC). The expression level of miR-195 is inversely correlated with HCC tumor size. We further show that miR-195 suppresses cancer cell proliferation and migration in vitro and reduces tumorigenicity and metastasis in vivo. Additionally, miR-195 may exert its tumor suppressive function by decreasing the expression of multiple NF-κB downstream effectors by way of the direct targeting of IKKα and TAB3. Conclusion: Multiple miRNAs are involved in the NF-κB signaling pathway and miR-195 plays important inhibitory roles in cancer progression and may be a potential therapeutic target. (Hepatology 2013;58:654–666)

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