Liu Hejing, Liu Yi, Zhou Yujia, Chen Xin, Pan Shuya, Zhou Qingfeng, Ji Huihui, Zhu Xueqiong
Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
Cell Death Discov. 2024 May 1;10(1):207. doi: 10.1038/s41420-024-01975-8.
Cervical cancer poses a serious threat to women's health globally. Our previous studies found that upregulation of TM7SF2, which works as an enzyme involved in the process of cholesterol biosynthesis expression, was highly correlated with cervical cancer. However, the mechanistic basis of TM7SF2 promoting cervical cancer progression via lipid metabolism remains poorly understood. Therefore, quantification of fatty acids and lipid droplets were performed in vitro and in vivo. The protein-protein interaction was verified by Co-IP technique. The mechanism and underlying signaling pathway of TM7SF2 via CPT1A associated lipid metabolism in cervical cancer development were explored using Western blotting, IHC, colony formation, transwell assay, and wound healing assay. This study reported that overexpression of TM7SF2 increased fatty acids content and lipid droplets both in vivo and in vitro experiments. While knockout of TM7SF2 obviously attenuated this process. Moreover, TM7SF2 directly bonded with CPT1A, a key enzyme in fatty acid oxidation, and regulated CPT1A protein expression in cervical cancer cells. Notably, the proliferation and metastasis of cervical cancer cells were elevated when their CPT1A expression was upregulated. Then, rescue assay identified that CPT1A overexpressed could enhance the cell viability and migration in TM7SF2-knockout cells. Furthermore, depletion of TM7SF2 significantly inhibited WNT and β-catenin proteins expression, which was enhanced by CPT1A-overexpressed. The proliferation and migration of cervical cancer cells were reversed in CPT1A-overexpressed cells with the treatment of MSAB, an inhibitor of Wnt/β-Catenin pathway. This study put forward an idea that TM7SF2-induced lipid reprogramming promotes proliferation and migration via CPT1A/Wnt/β-Catenin axis in cervical cancer, underlying the progression of cervical cancer.
宫颈癌在全球范围内对女性健康构成严重威胁。我们之前的研究发现，作为参与胆固醇生物合成表达过程的一种酶，TM7SF2的上调与宫颈癌高度相关。然而，TM7SF2通过脂质代谢促进宫颈癌进展的机制基础仍知之甚少。因此，我们在体外和体内对脂肪酸和脂滴进行了定量分析。通过免疫共沉淀（Co-IP）技术验证了蛋白质-蛋白质相互作用。利用蛋白质免疫印迹法（Western blotting）、免疫组化法（IHC）、集落形成实验、Transwell实验和伤口愈合实验，探讨了TM7SF2通过肉碱棕榈酰转移酶1A（CPT1A）相关脂质代谢在宫颈癌发生发展中的机制及潜在信号通路。本研究报道，在体内和体外实验中，TM7SF2的过表达均增加了脂肪酸含量和脂滴。而敲除TM7SF2明显减弱了这一过程。此外，TM7SF2直接与脂肪酸氧化中的关键酶CPT1A结合，并调节宫颈癌细胞中CPT1A蛋白的表达。值得注意的是，当宫颈癌细胞中CPT1A表达上调时，其增殖和转移能力增强。然后，挽救实验证实，过表达CPT1A可增强TM7SF2敲除细胞的细胞活力和迁移能力。此外，敲低TM7SF2显著抑制WNT和β-连环蛋白的蛋白表达，而过表达CPT1A可增强这种抑制作用。用Wnt/β-连环蛋白通路抑制剂MSAB处理过表达CPT1A的细胞后，宫颈癌细胞的增殖和迁移能力发生了逆转。本研究提出了一个观点，即TM7SF2诱导的脂质重编程通过CPT1A/Wnt/β-连环蛋白轴促进宫颈癌的增殖和迁移，这是宫颈癌进展的潜在机制。
