N6-甲基腺苷介导的 PAICS 上调通过 integrin-FAK 信号通路促进肺腺癌转移
N6-methyladenosine-mediated upregulation of PAICS promotes lung-adenocarcinoma metastasis via the integrin-FAK signaling.
作者
作者单位
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. zihupo1988@163.com.
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. huang_jian_an@163.com.
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. liuzeyisuda@163.com.
摘要
中文
肺腺癌（LUAD）是最常见的肺癌类型，常在晚期弥漫转移阶段确诊，侵袭性强且迅速致命，缺少早期诊断标志物和有效治疗靶点。磷酸核糖氨基咪唑羧化酶/磷酸核糖氨基咪唑琥珀酰胺合成酶（PAICS）是嘌呤从头合成中的重要双功能酶，快速分裂的肿瘤细胞高度依赖腺嘌呤和鸟嘌呤通路的从头合成。PAICS 已被发现在多种肿瘤中高表达，并被证实促进肿瘤增殖或转移。然而，PAICS 在 LUAD 中的具体作用机制尚不清楚。我们的研究发现，PAICS 的 mRNA 和蛋白水平在 LUAD 肿瘤组织中相较于癌旁正常组织显著上调。生物信息学分析显示，PAICS 高表达与 LUAD 转移相关，可作为 LUAD 患者诊断和预后评估的因素。PAICS 敲低抑制肿瘤细胞迁移和侵袭，而过表达则增强这些表型。机制上，PAICS 通过调控 Integrin α10（ITGA10）表达激活 Focal Adhesion Kinase（FAK）信号通路，从而促进肿瘤转移。FAK 抑制剂 Defactinib（VS6063）在体内成功抑制了 PAICS 过表达诱导的肺转移。此外，我们发现 LUAD 中 PAICS 的高表达受 m6A 修饰调控。METTL3（Methyltransferase-like 3）增强 PAICS mRNA 的修饰水平，IGF2BP2（Insulin-like growth factor 2 mRNA binding protein 2）在识别 m6A 修饰位点后结合其 mRNA，从而增加 mRNA 的稳定性和表达。这些结果为 PAICS 的生物学功能提供了有价值的见解，并为新的治疗途径提供了潜在方向。
English
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.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 9.1
- 新锐分区
- 1区