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

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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC4791267 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Gao Yang Y Wu Kaijie K Chen Yule Y Zhou Jiancheng J Du Chong C Shi Qi Q Xu Shan S Jia Jing J Tang Xiaoshuang X Li Feng F Hui Ke K He Dalin D Guo Peng P

Oncotarget 20151201 41

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 ...[more]

PMID: 26544730

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Project description:PurposeAngiogenesis actively contributes to tumor growth and metastasis. MACC1 was reported to be associated with tumor progression. In the present study, we aimed to investigate the expression and role of MACC1 in cholangiocarcinoma (CCA) and its correlation with angiogenesis.Patients and methodsWe investigated the expression and correlation of MACC1 and VEGFA in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and in 7 paired frozen CCA and matched paracarcinoma tissues. Immunohistochemistry (IHC) was used to examine MACC1 and VEGFA expression as well as microvessel density (MVD) in 122 paraffin-embedded CCA samples. Western blotting, real-time qPCR and ELISA were performed to investigate the effect of MACC1 knockdown on VEGFA expression and secretion in CCA cells. Subsequently, we collected conditioned medium from cells with MACC1 knockdown and used it in angiogenesis assays.ResultsThe expression levels of both MACC1 and VEGFA were significantly upregulated in the TCGA and GEO datasets and in the 7 paired frozen CCA tissues compared to the matched paracarcinoma tissues, and MACC1 was significantly correlated with VEGFA. IHC showed that high expression of MACC1 and VEGFA was significantly correlated with lymph node metastasis (P<0.05 and P<0.01) and worse survival (P<0.01, P<0.05) in patients with CCA. We further verified that MACC1 was significantly correlated with VEGFA (P<0.01) and MVD (P<0.01) in clinical samples. Western blotting, real-time qPCR and ELISA results showed that MACC1 knockdown in CCA cells significantly decreased the protein and mRNA expression of VEGFA and reduced the VEGFA concentration in conditioned medium. Moreover, angiogenesis assays showed that conditioned medium from CCA cells with MACC1 knockdown decreased the number of tubes formed.ConclusionOur results indicate that MACC1 and VEGFA expression are upregulated in CCA. Moreover, MACC1 is an independent predictor of overall survival and facilitates angiogenesis in CCA by upregulating of VEGFA.

Project description:The purpose of our study is to elucidate the expression of lncRNA00518 (lnc00518) in the bladder cancer, and its potential mechanism in regulating the development of bladder cancer. The expression of lnc00518 in bladder cancer tissues and cells was examined by qRT-PCR. Correlation between lnc00518 expression with clinicopathologic characteristics and prognosis of bladder cancer patients was analyzed. In vitro effects of lnc00518 on the cellular behaviors of bladder cancer cells were explored. Moreover, in vivo effect of lnc00518 was evaluated by subcutaneous tumorigenesis in nude mice. The possible miRNA targets of lnc00518 were predicted by bioinformatics and further confirmed by dual-luciferase reporter gene assay, RIP and rescue experiments. Lnc00518 was highly expressed in bladder cancer tissues and cells. Lnc00518 expression was correlated with TNM staging and histological grade of bladder cancer. Besides, the overall survival was lower in bladder cancer patients with high expression of lnc00518 relative to those with low expression. Overexpression of lnc00518 enhanced proliferative, invasive, migratory potentials and clonality, but shortened G0/G1 phase of bladder cancer cells. Lnc00518 knockdown obtained the opposite trends. In vivo experiments revealed that lnc00518 knockdown inhibited subcutaneous tumorigenesis in nude mice. QRT-PCR results indicated that lnc00518 expression was negatively correlated with miRNA-101 expression in bladder cancer cells. Through dual-luciferase reporter gene assay and RIP, we confirmed the binding between lnc00518 and miRNA-101. Furthermore, EZH2 was verified to be the target of miRNA-101. MiRNA-101 knockdown reversed the inhibitory roles of lnc00518 knockdown in proliferative, migratory and invasive potentials of bladder cancer cells. Lnc00518 is highly expressed in bladder cancer and can be served as a predictor of poor prognosis. Lnc00518 promotes the proliferative, invasive and migratory potentials of bladder cancer by upregulating EZH2 via competitively binding to miRNA-101.

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

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

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