Cytotoxic necrotizing factor 1 promotes bladder cancer angiogenesis through activating RhoC
作者单位：Department of ImmunologyTianjin Key Laboratory of Cellular and Molecular ImmunologySchool of Basic Medical SciencesTianjin Medical University
会议名称：《第十三届全国免疫学学术大会》
会议日期：2018年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：cytotoxic necrotizing factor 1 uropathogenic Escherichia coli bladder cancer Angiogenes
摘 要：Background & Aims: Uropathogenic Escherichia coli(UPEC) is the leading cause of urinary tract infections(UTIs).UTIs caused by UPEC usually induce cystitis and prostatitis.In a mouse model, UPEC accelerate prostate cancer progression.Cytotoxic necrotizing factor 1(CNF1) is a key UPEC toxin.CNF1 induce Rho GTPases activation by deamidating specific glutamine residues.RhoC is an important member of the RhoGTPase family.RhoC play important roles in tumor progression, such as facilitating the invasion and metastasis of tumor cells and promoting tumor angiogenesis.The study aims to investigate the role of CNF1 in angiogenesis of bladder cancer and explore the signaling mechanisms through which CNF1 affect bladder cancer angiogenesis.Methods: Cells were incubated with purified CNF1 under hypoxic conditions, and VEGF secretion was examined by ELISA.The medium was collected and capillary-like structure formation in HUVECs was examined by tube formation assay.HIF1α and RhoC activation was evaluated by western blotting, qPCR, and pulldown assays.Subcutaneous tumor mouse model was used for in vivo verification.Results: CNF1 promoted the migration and invasion of bladder cancer cells and vascular endothelial cells in vitro.CNF1 induced VEGF secretion in bladder cancer cells and subsequently promoted angiogenesis in HUVECs.And HIF1α was involved in CNF1-induced VEGF secretion.CNF1 up-regulated the expression of HIF1α by activating RhoC.RhoC activation modulated the expression of HIF1α and the secretion of VEGF.Moreover, in a subcutaneous tumor mouse model, active RhoC promoted the tumor-associated angiogenesis of bladder cancer in vivo.Conclusions: CNF1 promotes bladder cancer angiogenesis via activating RhoC-HIF1α-VEGF axis.This finding provides a novel mechanism of UPEC-accelerated bladder cancer progression and identifies new therapeutic targets for bladder cancer with complicated bladder infections.