Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription.
Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription.
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超越增殖：KLF5 通过直接调节 VEGFA 转录促进膀胱癌的血管生成
DOI：
10.18632/oncotarget.6101
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发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
Guo P
中科院分区：
文献类型：
--
作者：
Gao Y;Wu K;Chen Y;Zhou J;Du C;Shi Q;Xu S;Jia J;Tang X;Li F;Hui K;He D;Guo P
大量证据表明KLF 5在多种癌症中调节细胞增殖的关键作用，然而，其在癌症发展的其他方面的其他作用仍有待进一步阐明。在这项研究中，我们发现，KLF 5是必不可少的癌细胞-内皮细胞在体外的相互作用和肿瘤血管生成的裸鼠的基础上慢病毒介导的KLF 5敲低膀胱癌细胞模型。此外，KLF 5不足消除了膀胱癌细胞诱导兔角膜新生血管形成的能力。在机制上，促血管生成因子VEGFA被鉴定为KLF 5的直接下游靶点，其结合于VEGFA启动子的GC盒和CACCC元件并调节其转录活性。此外，通过免疫组化检测和TCGA和GEO数据的统计分析，KLF 5和VEGFA在人膀胱癌组织中的表达呈正相关。此外，我们发现膀胱癌中的两个关键通路RTK/RAS/MAPK和PI 3 K/Akt可能通过KLF 5-VEGFA轴传递其致癌信号。综上所述，我们的研究结果表明，KLF 5通过直接调节VEGFA转录促进膀胱癌血管生成，并建议KLF 5可能是一个新的治疗靶点，抑制膀胱癌血管生成。
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.