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WTAP-mediated m6A modification on circCMTM3 inhibits hepatocellular carcinoma ferroptosis by recruiting IGF2BP1 to increase PARK7 stability

  • Shuwei Chen
    Affiliations
    Department of Hepatobiliary Surgery, Chenzhou First People's Hospital of Hunan Province, Chenzhou, Hunan 423000, PR China
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  • Hongxiang Xia
    Affiliations
    Interventional Diagnosis and Treatment Center, Chenzhou First People's Hospital of Hunan Province, Chenzhou, Hunan 423000, PR China
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  • Langqing Sheng
    Correspondence
    Corresponding author at: Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, 87th Xiangya road, Changsha, Hunan 410008, PR China.
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China

    International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment and Standards, Changsha, Hunan 410008, PR China
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Published:December 30, 2022DOI:https://doi.org/10.1016/j.dld.2022.12.005

      Abstract

      Background

      Hepatocellular carcinoma (HCC) has poor prognosis and high mortality. CircCMTM3 was significantly up-regulated in HCC. However, the mechanism of circCMTM3 in HCC is not full elucidated.

      Methods

      The expression level of circCMTM3, PARK7, GPX4, and Ki67 in HCC cells and tissues were quantified by qRT-PCR, IHC, and Western blotting. The level of GSH, total iron, Fe2+, and MDA were detected by their kits. CCK-8 and flow cytometry analysis were used to evaluated cell proliferation and lipid ROS level, respectively. m6A level of circCMTM3 was assessed by MeRIP-PCR. RNA pulldown, RIP, and FISH detected the interaction between circCMTM3, WTAP, and PARK7. Tumor xenograft model was constructed to validate the function of cicrCMTM3 and WTAP.

      Results

      CircCMTM3 and WTAP were enhanced in HCC tissues and cells. Knockdown of WTAP inhibited m6A modification of circCMTM3, which promoted HCC ferroptosis. circCMTM3 silencing suppressed the expression and stability of PARK7 through binding with IGF2BP1 in HCC cells, which finally induced ferroptosis. In vivo studies demonstrated that silencing WTAP and circCMTM3 suppressed tumor growth and promoted HCC ferroptosis in nude mice by regulating PARK7 signaling.

      Conclusion

      CircCMTM3 promoted the carcinogenesis through inhibiting ferroptosis by recruiting IGF2BP1 to increase PARK7 stability in HCC, suggesting that cicrCMTM3 may be an important marker for HCC treatment.

      Keywords

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