Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription.

Yang Gao,Ke Hui,Feng Li,Shan Xu,Peng Guo,Jiancheng Zhou,Chong Du,Jing Jia,Dalin He,Yule Chen,Xiaoshuang Tang,Qi Shi,Kaijie Wu

doi:10.18632/oncotarget.6101

Abstract

Abundant evidence has demonstrated critical roles of KLF5 in regulating cell proliferation in various cancers, however, its additional roles in other aspects of cancer development remain to be further clarified. In this study, we found that KLF5 was essential for cancer cell-endothelial cell interaction in vitro and tumor angiogenesis in nude mice based on lentivirus-mediated KLF5 knockdown bladder cancer cell models. Moreover, KLF5 insufficiency abolished the ability of bladder cancer cells to induce neovascularization in rabbit cornea. Mechanistically, the pro-angiogenic factor VEGFA was identified as a direct downstream target of KLF5, which bound to GC-boxes and CACCC elements of VEGFA promoter and regulated its transcriptional activity. In addition, there was a positive correlation between KLF5 and VEGFA expression in human bladder cancer tissues by immunohistochemistry assay and statistical analysis from TCGA and GEO data. Furthermore, we found that two pivotal pathways in bladder cancer, RTKs/RAS/MAPK and PI3K/Akt, might convey their oncogenic signaling through KLF5-VEGFA axis. Taken together, our results indicate that KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription and suggest that KLF5 could be a novel therapeutic target for angiogenesis inhibition in bladder cancer.

Highlights

Bladder cancer is one of the most common forms of urological cancer worldwide, with estimated 386,300 new cases and 150,200 deaths per year [1]
We found that pro-proliferative factor KLF5 was required for bladder cancer cell growth, and essential for the interaction between bladder cancer cells and endothelial cells in vitro and tumor angiogenesis in the xenografts in nude mice and in rabbit cornea
We demonstrated that several GC boxes and CACCC elements in promoter of vascular endothelial growth factor A (VEGFA) served as binding sites for KLF5, and knockdown of KLF5 significantly impaired VEGFA promoter transcription activity

Summary

Introduction

Bladder cancer is one of the most common forms of urological cancer worldwide, with estimated 386,300 new cases and 150,200 deaths per year [1]. In the United States, 74,000 new bladder cancer cases and 16,000 cancer deaths are estimated to occur in 2015 [2]. Abundant evidence has proved that NMIBC and MIBC have distinct genetic alterations [4], even in MIBC, distinct molecular subtypes with variable clinical outcomes and responses to conventional chemotherapy have been suggested [5]. All these features reveal the complex characteristics of bladder cancers. No targeted agent has been approved for treatment of this disease in nearly thirty years, showing an urgent need of research progress to improve diagnosis and treatment of bladder cancer

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Results

Conclusion