Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription
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Yang Gao1,2,*, Kaijie Wu1,2,*, Yule Chen1,2, Jiancheng Zhou1, Chong Du1, Qi Shi1, Shan Xu1,2, Jing Jia1, Xiaoshuang Tang1, Feng Li1, Ke Hui1, Dalin He1,2, Peng Guo1,2
1Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
2Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi, China
*These authors have contributed equally to this work
Peng Guo, e-mail: [email protected]
Dalin He, e-mail: [email protected]
Keywords: KLF5, bladder cancer, VEGFA, angiogenesis, endothelial cell
Received: May 04, 2015 Accepted: October 17, 2015 Published: October 31, 2015
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.
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