2. Academic Validation
  3. WTAP-mediated m6A modification on circCMTM3 inhibits hepatocellular carcinoma ferroptosis by recruiting IGF2BP1 to increase PARK7 stability

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

  • Dig Liver Dis. 2022 Dec 29;S1590-8658(22)00827-1. doi: 10.1016/j.dld.2022.12.005.
Shuwei Chen 1,  Hongxiang Xia 2,  Langqing Sheng 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Chenzhou First People's Hospital of Hunan Province, Chenzhou, Hunan 423000, PR China.
  • 2 Interventional Diagnosis and Treatment Center, Chenzhou First People's Hospital of Hunan Province, Chenzhou, Hunan 423000, PR China.
  • 3 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. Electronic address: [email protected].
PMID: 36586770 DOI: 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

CircCMTM3; Ferroptosis; Hepatocellular carcinoma; M(6)A modification; PARK7 signaling.

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