Gao Yang, Wu Kaijie, Chen Yule, Zhou Jiancheng, Du Chong, Shi Qi, Xu Shan, Jia Jing, Tang Xiaoshuang, Li Feng, Hui Ke, He Dalin, Guo Peng
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
Oncotarget. 2015 Dec 22;6(41):43791-805. doi: 10.18632/oncotarget.6101.
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.
大量证据表明KLF5在调控多种癌症的细胞增殖中发挥关键作用，然而，其在癌症发展其他方面的额外作用仍有待进一步阐明。在本研究中，基于慢病毒介导的KLF5敲低膀胱癌细胞模型，我们发现KLF5在体外对于癌细胞-内皮细胞相互作用以及裸鼠肿瘤血管生成至关重要。此外，KLF5功能不足消除了膀胱癌细胞在兔角膜中诱导新血管形成的能力。从机制上讲，促血管生成因子VEGFA被确定为KLF5的直接下游靶点，KLF5与VEGFA启动子的GC盒和CACCC元件结合并调节其转录活性。此外，通过免疫组织化学分析以及来自TCGA和GEO数据的统计分析，发现人膀胱癌组织中KLF5与VEGFA表达呈正相关。此外，我们发现膀胱癌中的两条关键信号通路RTKs/RAS/MAPK和PI3K/Akt可能通过KLF5-VEGFA轴传递其致癌信号。综上所述，我们的结果表明KLF5通过直接调节VEGFA转录促进膀胱癌血管生成，并提示KLF5可能是膀胱癌血管生成抑制的一个新的治疗靶点。
