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<p>KRAS N6-methyladenosine (m<sup>6</sup>A) modification has emerged as a crucial epigenetic regulator in cancer progression, but its role in cervical cancer epithelial-mesenchymal transition (EMT) and stromal remodeling remains unclear. This study explored how METTL3-dependent m<sup>6</sup>A methylation of KRAS influences metastasis through the TGF-β/SMAD/SNAIL pathway. RNA sequencing (RNA-seq) and MeRIP-seq revealed that METTL3 knockdown significantly reduces KRAS m<sup>6</sup>A levels and suppresses TGF-β/SMAD pathway activation. Functional assays, including Western blot, immunofluorescence, Transwell, and scratch tests, demonstrated that METTL3 depletion inhibits cell migration, invasion, and EMT marker expression. Co-immunoprecipitation confirmed that m<sup>6</sup>A modification facilitates interactions between KRAS, SMAD2/3, and SNAIL. In vivo models showed reduced tumor growth and pulmonary metastasis upon METTL3 silencing. These findings define a novel METTL3-KRAS-TGF-β/SMAD/SNAIL axis in cervical cancer, offering new insights into m<sup>6</sup>A-mediated metastasis and potential therapeutic targets.</p><p></p>

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m6A epitranscriptomic regulation of KRAS by METTL3 promotes EMT and stromal remodeling through TGF-β/SMAD signaling in cervical cancer

  • 期刊论文

  • 发表日期：

    2026年1月3日

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  • Yangmei Gong,
  • Jie Wu,
  • Yi Hu

摘要

KRAS N6-methyladenosine (m6A) modification has emerged as a crucial epigenetic regulator in cancer progression, but its role in cervical cancer epithelial-mesenchymal transition (EMT) and stromal remodeling remains unclear. This study explored how METTL3-dependent m6A methylation of KRAS influences metastasis through the TGF-β/SMAD/SNAIL pathway. RNA sequencing (RNA-seq) and MeRIP-seq revealed that METTL3 knockdown significantly reduces KRAS m6A levels and suppresses TGF-β/SMAD pathway activation. Functional assays, including Western blot, immunofluorescence, Transwell, and scratch tests, demonstrated that METTL3 depletion inhibits cell migration, invasion, and EMT marker expression. Co-immunoprecipitation confirmed that m6A modification facilitates interactions between KRAS, SMAD2/3, and SNAIL. In vivo models showed reduced tumor growth and pulmonary metastasis upon METTL3 silencing. These findings define a novel METTL3-KRAS-TGF-β/SMAD/SNAIL axis in cervical cancer, offering new insights into m6A-mediated metastasis and potential therapeutic targets.