胸腺嘧啶合成酶调控乳腺癌细胞转移的作用及机制

The role of thymidylate synthase in regulating breast cancer migration

胸腺嘧啶合成酶(thymidylate synthase,TYMS)是胸苷酸从头合成途径的关键酶,对于DNA合成和修复非常必要.TYMS在多种肿瘤中表达上调与患者的不良预后相关.许多研究证实,高表达TYMS促进了肿瘤生长和化疗抵抗,然而它对于乳腺肿瘤细胞转移的作用目前还存在争议.本研究探讨了TYMS调控乳腺癌细胞转移的作用及机制.通过对网上公开数据库的分析发现,高表达TYMS与患者较短的无转移生存相关.在体外细胞模型中,敲低TYMS的表达可抑制乳腺癌细胞的增殖、转移及上皮间质转化(epithelial-mesenchymal transition,EMT)过程.RNA测序数据分析显示,HIF1α-CXCL12-ACKR3通路分子、PLK1和SMAD5在TYMS敲低的MCF-7细胞中表达下调,提示这些分子作为TYMS的下游效应分子介导了TYMS调控的细胞增殖、迁移和EMT.

Thymidylate synthase(TYMS)is a fundamental enzyme of the sole de novo pathway for thymidylate production.It is essential for DNA synthesis and repair and is known as a target of chemotherapy.TYMS is greatly elevated in a diverse range of human cancers and associated with poor clinical outcomes.Accumulating evidence has proved that higher expression of TYMS contributed to tumor growth and chemoresistance.However,the consequences of elevated TYMS on breast cancer metastasis are still controversial.We find in the present study that higher TYMS in breast cancer is associated with shorter distant metastasis-free survival(DMFS)based on analysis of the publicly available online databases.The in vitro experiments show that knockdown of TYMS decreases proliferation,migration and epithelial-mesenchymal transition(EMT)in breast cancer cells.RNA sequence analysis of the differentially expressed genes reveals that HIF1α-CXCL12-ACKR3 signaling molecules,PLK1 and SMAD5,are downregulated in TYMS knockdown MCF-7 cells compared with that in control cells,indicating that these molecules serve as downstream effectors of TYMS and mediate TYMS-regulated cell proliferation,migration and EMT.