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Tumor-suppressor p53 specifically binds to miR-29c-3p and reduces ADAM12 expression in hepatocellular carcinoma

  • Author Footnotes
    1 These authors contributed equally to this work.
    Jinhui Che
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Zhan Su
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Weizhong Yang
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Lu Xu
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Yunjiu Li
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Haihong Wang
    Correspondence
    Corresponding author at: Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, No. 131, Huancheng Road, Gulou District, Xuzhou 221000, Jiangsu Province, PR China.
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Wuyuan Zhou
    Correspondence
    Corresponding author at: Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, No. 131, Huancheng Road, Gulou District, Xuzhou 221000, Jiangsu Province, PR China.
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Xuzhou City Cancer Hospital, Xuzhou 221000, PR China
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Background

      Hepatocellular carcinoma (HCC) is an extremely aggressive malignant tumor associated with high migratory and invasive potential. The present study intends to explore regulatory mechanism of p53/microRNA (miR)-29c-3p/A disintegrin and metalloproteinase 12 (ADAM12) axis in HCC based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology.

      Methods

      Putative miR-29c-3p binding sites on ADAM12 3′UTR were verified by a luciferase assay. The binding affinity of p53 to miR-29c-3p was assessed based on CRISPR/Cas9 technology to construct a p53 knockout (p53−/−) HCCLM3 cell line. Furthermore, the effect of p53/miR-29c-3p/ADAM12 was assessed on maligant phenotypes in vitro and tumor formation and metastasis in nude mice.

      Results

      ADAM12 was highly expressed but miR-29c-3p was poorly expressed in HCC. miR-29c-3p inhibited migratory and invasive abilities of HCC cells by targeting ADAM12 expression. p53 was found to target and upregulate miR-29c-3p, thus downregulating ADAM12 and conferring inhibitory effect on HCC cell activities. Moreover, ADAM12 knockout or p53 overexpression reduced HCC tumor formation and metastasis, which were reversed by further silencing of miR-29c-3p.

      Conclusion

      The identification of the p53/miR-29c-3p/ADAM12 axis in migration and invasion of HCC may potentially further our understanding of mechanisms underpinning HCC, and also bear translational value as novel molecular targets.

      Keywords

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