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FTO downregulation-mediated m6A modification resulting in enhanced hepatocellular carcinoma invasion

  • 0Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China.
Cell & Bioscience +

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May 2, 2025

|

May 2, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Elevated N6-methyladenosine (m6A) levels correlate with poor prognosis in hepatocellular carcinoma (HCC). The demethylase FTO acts as a tumor suppressor, with its downregulation promoting HCC progression and metastasis.

Area Of Science

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background

  • N6-methyladenosine (m6A) modification dysregulation is linked to various cancers, including hepatocellular carcinoma (HCC).
  • The role of m6A in HCC prognosis and its underlying molecular mechanisms, especially involving the FTO demethylase, remain to be fully elucidated.

Purpose Of The Study

  • To investigate the prognostic significance of m6A modifications in HCC.
  • To explore the functional role and molecular mechanisms of the FTO demethylase in HCC progression and metastasis.

Main Methods

  • Analyzed m6A expression in 323 HCC patients via immunohistochemistry (IHC).
  • Quantified m6A-related gene expression (FTO, ALKBH5, METTL3, METTL14) in 120 paired HCC tissues using qRT-PCR.
  • Assessed FTO's impact on HCC cell behavior (proliferation, invasion, metastasis) in vitro and in vivo using genetically modified cell lines and mouse models.

Main Results

  • Elevated m6A levels were observed in 57.3% of HCC tissues and correlated with poorer overall survival and recurrence-free survival.
  • FTO demethylase was significantly downregulated in HCC, particularly in metastatic cell lines.
  • FTO overexpression suppressed HCC cell proliferation, migration, and invasion, and reduced tumor growth/metastasis in vivo, partly via downregulation of VEGFA.

Conclusions

  • Aberrant m6A modifications, driven by FTO downregulation, promote HCC progression and metastasis.
  • FTO functions as a tumor suppressor in HCC by negatively regulating VEGFA, suggesting its therapeutic potential.
  • m6A modifications are significant in HCC, providing a basis for developing targeted therapies.

Keywords:

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