Cancer Management and Research (2020-12-01)

METTL14 Inhibits Hepatocellular Carcinoma Metastasis Through Regulating EGFR/PI3K/AKT Signaling Pathway in an m6A-Dependent Manner

  • Shi Y,
  • Zhuang Y,
  • Zhang J,
  • Chen M,
  • Wu S

Journal volume & issue
Vol. Volume 12
pp. 13173 – 13184

Abstract

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Yuntao Shi,1,* Yingying Zhuang,2,* Jialing Zhang,1 Mengxue Chen,1 Shangnong Wu1 1Department of Gastroenterology, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Huai’an, People’s Republic of China; 2Department of Medical Imaging, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Huai’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shangnong WuDepartment of Gastroenterology, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, No. 1, Huanghe West Road, Huai’an 223300, People’s Republic of ChinaTel +86 517-80872251Email [email protected]: Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths worldwide. N6-methyladenosine (m6A) RNA methylation is the most common modification of messenger RNAs (mRNAs). The prognosis of HCC patients with metastasis remains poor. Our study aimed to elucidate the regulatory role of m6A on HCC metastasis.Patients and Methods: All HCC patients were enrolled from The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University. The expression levels of gene were tested by quantitative polymerase chain reaction (qPCR), Western blot, or immunohistochemistry (IHC) analysis. Wound healing assay, Transwell invasion assay, and lung metastasis model were implemented to investigate the migration and invasion ability of HCC cells. Candidate targets were selected by a comprehensive analysis of RNA-sequencing and m6A-sequencing of HepG2 cells.Results: In this study, we demonstrated that METTL14 was significantly downregulated in HCC and significantly associated with the prognosis of HCC patients. METTL14 knockdown promoted the migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells in vitro and in vivo. In addition, overlapping RNA-sequencing and m6A-sequencing data, we identified EGFR as a direct target of METTL14 in HCC. Mechanistically, METTL14 was found to inhibit HCC cell migration, invasion, and EMT through modulating EGFR/PI3K/AKT signaling pathway in an m6A-dependent manner.Conclusion: Targeting METTL14/EGFR/PI3K/AKT signaling pathway may facilitate the development of a new treatment strategy against the metastasis of HCC.Keywords: hepatocellular carcinoma, N6-methyladenosine, METTL14, EGFR

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