Abstract
BackgroundKLF5 is a basic transcriptional factor that regulates multiple physiopathological processes. Our recent study showed that deletion of Klf5 in mouse prostate promotes tumorigenesis initiated by the deletion of Pten. While molecular characterization of Klf5-null tumors suggested that angiogenesis was partially responsible for tumor promotion, the precise function and mechanism of KLF5 deletion in prostate tumor angiogenesis remain unclear.ResultsApplying histological staining to Pten-null mouse prostates, we observed that deletion of Klf5 significantly increased the number of microvessels, accompanied by the upregulation of multiple angiogenesis-related genes based on microarray analysis with MetaCore software. In human umbilical vein endothelial cells (HuVECs), tube formation and migration, both of which are indicators of angiogenic activities, were decreased by conditioned media from PC-3 and DU 145 human prostate cancer cells with KLF5 overexpression, but increased by media from cells with KLF5 knockdown. HIF1α, a key angiogenesis inducer, was upregulated by KLF5 loss at the protein but not the mRNA level in both mouse tissues and human cell lines, as determined by immunohistochemical staining, real-time RT-PCR and Western blotting. Consistently, KLF5 loss also upregulated VEGF and PDGF, two pro-angiogenic mediators of HIF1α function, as analyzed by immunohistochemical staining in mouse tissues and ELISA in conditioned media. Mechanistically, AKT activity, which caused the accumulation of HIF1α, was increased by KLF5 knockout or knockdown but decreased by KLF5 overexpression. PI3K/AKT inhibitors consistently abolished the effects of KLF5 knockdown on angiogenic activity, HIF1α accumulation, and VEGF and PDGF expression.ConclusionKLF5 loss enhances tumor angiogenesis by attenuating PI3K/AKT signaling and subsequent accumulation of HIF1α in PTEN deficient prostate tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0365-6) contains supplementary material, which is available to authorized users.
Highlights
Angiogenesis, the process of forming new blood vessels from pre-existing vessels, is vital for development, tissue wound healing, and tumor initiation and progression [1]
Klf5 deletion promotes angiogenesis initiated by Pten deletion in mouse prostate tumors To test whether Klf5 deletion plays a role in tumor angiogenesis, we first examined H&E stained tissue sections for the number of intraepithelial blood vessels, indicated by histological appearance and the presence of red blood cells between wildtype tissues and those with
This result indicates that Klf5 deletion promotes angiogenesis in both prostate tumors and mouse prostatic intraepithelial neoplasia (mPIN) induced by Pten deletion
Summary
Angiogenesis, the process of forming new blood vessels from pre-existing vessels, is vital for development, tissue wound healing, and tumor initiation and progression [1]. Tumor angiogenesis is activated by multiple proangiogenic secretory factors including VEGF, PDGF-B, bFGF and TNF-α, which are all transcriptionally activated by hypoxia inducible factor 1 (HIF1) [2], composed of HIF1α and HIF1β subunits. A better understanding of the molecular basis of angiogenesis should improve the development of antiangiogenesis-based cancer therapy. KLF5 is a basic transcriptional factor that regulates multiple physiopathological processes. Our recent study showed that deletion of Klf in mouse prostate promotes tumorigenesis initiated by the deletion of Pten. While molecular characterization of Klf5-null tumors suggested that angiogenesis was partially responsible for tumor promotion, the precise function and mechanism of KLF5 deletion in prostate tumor angiogenesis remain unclear
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