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<p>Lung adenocarcinoma (LUAD) is the most common type of lung cancer, often diagnosed in the advanced stage of diffuse metastasis, highly aggressive and rapidly fatal, lacking early diagnostic markers and effective therapeutic targets. Enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in purine de novo synthesis, and rapidly dividing cancer cells are heavily dependent on de novo synthesis of the adenine and guanine pathways. <i>PAICS</i> has been found to be highly expressed in a variety of cancers and has been shown to promote cancer proliferation or metastasis. However, the specific mechanism of action of <i>PAICS</i> in LUAD is unknown. Our study revealed that <i>PAICS</i> mRNA and protein levels were significantly increased in LUAD tumor tissues compared to adjacent normal tissues. Bioinformatics analysis showed that high <i>PAICS</i> expression was associated with LUAD metastasis and could be used as a factor for diagnosis and assessment of prognosis in LUAD patients. <i>PAICS</i> knockdown suppressed tumor cell migration and invasion, whereas overexpression enhanced these phenotypes. Mechanistically, <i>PAICS</i> promotes tumor metastasis by activating the Focal Adhesion Kinase (FAK) signaling through regulating the expression of Integrin α10 (<i>ITGA10</i>). FAK inhibitor Defactinib (VS6063) successfully inhibited <i>PAICS</i> overexpression-induced lung metastasis in vivo. In addition, we found that the high expression of <i>PAICS</i> in LUAD was regulated by m<sup>6</sup>A modification. METTL3 (Methyltransferase-like 3) enhances the modification level of <i>PAICS</i> mRNA and IGF2BP2 (Insulin-like growth factor 2 mRNA binding protein 2) binds to its mRNA upon recognition of the m<sup>6</sup>A modification site, which increased the stability of the mRNA and the expression. These results provide valuable insights into the biological functions of <i>PAICS</i> and potential avenues for new therapeutic approaches.</p>

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N6-methyladenosine–mediated upregulation of PAICS promotes lung-adenocarcinoma metastasis via the integrin-FAK signaling

  • 期刊论文

  • 发表日期：

    2026年7月23日

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  • Mengzhu Zhang,
  • Jianjie Zhu,
  • Huiling Zhang,
  • Jiansheng Zhang,
  • Jian Zhao,
  • Qiongju Chen,
  • Yuanyuan Zeng,
  • Jianjun Li,
  • Jian-an Huang,
  • Zeyi Liu

摘要

Lung adenocarcinoma (LUAD) is the most common type of lung cancer, often diagnosed in the advanced stage of diffuse metastasis, highly aggressive and rapidly fatal, lacking early diagnostic markers and effective therapeutic targets. Enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in purine de novo synthesis, and rapidly dividing cancer cells are heavily dependent on de novo synthesis of the adenine and guanine pathways. PAICS has been found to be highly expressed in a variety of cancers and has been shown to promote cancer proliferation or metastasis. However, the specific mechanism of action of PAICS in LUAD is unknown. Our study revealed that PAICS mRNA and protein levels were significantly increased in LUAD tumor tissues compared to adjacent normal tissues. Bioinformatics analysis showed that high PAICS expression was associated with LUAD metastasis and could be used as a factor for diagnosis and assessment of prognosis in LUAD patients. PAICS knockdown suppressed tumor cell migration and invasion, whereas overexpression enhanced these phenotypes. Mechanistically, PAICS promotes tumor metastasis by activating the Focal Adhesion Kinase (FAK) signaling through regulating the expression of Integrin α10 (ITGA10). FAK inhibitor Defactinib (VS6063) successfully inhibited PAICS overexpression-induced lung metastasis in vivo. In addition, we found that the high expression of PAICS in LUAD was regulated by m6A modification. METTL3 (Methyltransferase-like 3) enhances the modification level of PAICS mRNA and IGF2BP2 (Insulin-like growth factor 2 mRNA binding protein 2) binds to its mRNA upon recognition of the m6A modification site, which increased the stability of the mRNA and the expression. These results provide valuable insights into the biological functions of PAICS and potential avenues for new therapeutic approaches.