Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Biol Toxicol. 2024 Aug 2;40(1):62. doi: 10.1007/s10565-024-09899-w.
Increased activity of the transcription factor FOXC1 leads to elevated transcription of target genes, ultimately facilitating the progression of various cancer types. However, there are currently no literature reports on the role of FOXC1 in renal cell carcinoma.
By using RT-qPCR, immunohistochemistry and Western blotting, FOXC1 mRNA and protein expression was evaluated. Gain of function experiments were utilized to assess the proliferation and metastasis ability of cells. A nude mouse model was created for transplanting tumors and establishing a lung metastasis model to observe cell proliferation and spread in a living organism. Various techniques including biological analysis, CHIP assay, luciferase assay, RT-qRCR and Western blotting experiments were utilized to investigate how FOXC1 contributes to the transcription of ABHD5 on a molecular level. FOXC1 was assessed by Western blot for its impact on AMPK/mTOR signaling pathway.
FOXC1 is down-regulated in RCC, causing unfavorable prognosis of patients with RCC. Further experiments showed that forced FOXC1 expression significantly restrains RCC cell growth and cell metastasis. Mechanically, FOXC1 promotes the transcription of ABHD5 to activate AMPK signal pathway to inhibit mTOR signal pathway. Finally, knockdown of ABHD5 recovered the inhibitory role of FOXC1 overexpression induced cell growth and metastasis suppression.
In general, our study demonstrates that FOXC1 exerts its tumor suppressor role by promoting ABHD5 transcription to regulating AMPK/mTOR signal pathway. FOXC1 could serve as both a diagnostic indicator and potential treatment focus for RCC.
转录因子 FOXC1 的活性增加会导致靶基因转录水平升高，最终促进多种癌症类型的进展。然而，目前尚无文献报道 FOXC1 在肾细胞癌中的作用。
通过 RT-qPCR、免疫组织化学和 Western blot 检测 FOXC1 mRNA 和蛋白表达。利用 gain of function 实验评估细胞的增殖和转移能力。建立裸鼠移植瘤和肺转移模型，观察细胞在体内的增殖和扩散。利用生物分析、CHIP 检测、荧光素酶检测、RT-qPCR 和 Western blot 实验等多种技术，研究 FOXC1 如何在分子水平上促进 ABHD5 的转录。通过 Western blot 检测 FOXC1 对 AMPK/mTOR 信号通路的影响。
FOXC1 在 RCC 中下调，导致 RCC 患者预后不良。进一步的实验表明，强制表达 FOXC1 可显著抑制 RCC 细胞的生长和转移。机制上，FOXC1 促进 ABHD5 的转录，激活 AMPK 信号通路，抑制 mTOR 信号通路。最后，敲低 ABHD5 恢复了 FOXC1 过表达诱导的细胞生长和转移抑制作用。
总的来说，我们的研究表明，FOXC1 通过促进 ABHD5 转录来调节 AMPK/mTOR 信号通路发挥其肿瘤抑制作用。FOXC1 可以作为 RCC 的诊断指标和潜在治疗靶点。
