Abstract
Tumor angiogenesis plays a critical role in hepatocellular carcinoma (HCC) development and progression, but its mechanism is unclear. Krüppel-like factor 8 (KLF8) is a transcription factor that plays an important role in HCC progression. Here, we investigated the role of KLF8 in angiogenesis in HCC and its possible mechanism. Immunohistochemistry, quantitative RT-PCR, western blotting, promoter reporter assays, chromatin immunoprecipitation (ChIP), and chicken chorioallantoic membrane (CAM) and nude mouse tumor models were used to show that the mRNA and protein expression levels of KLF8 and VEGFA are highly correlated in HCC tissue samples. The up-regulation of KLF8 increased VEGFA protein levels and induced VEGFA promoter activity by binding to the CACCC region of the VEGFA promoter. In addition, KLF8 regulated HIF-1α and Focal adhesion kinase (FAK) expression. The PI3K/AKT inhibitor LY294002 inhibited KLF8-induced VEGFA expression, whereas PI3K/AKT signaling pathway proteins, such as P-PDK1(Ser241) and P-AKT(Thr308), were decreased significantly. KLF8-overexpressing HCC cells had a higher potential for inducing angiogenesis. Thus, our results indicate that KLF8 may induce angiogenesis in HCC by binding to the CACCC region of the VEGFA promoter to induce VEGFA promoter activity and through FAK to activate PI3K/AKT signaling to regulate HIF-1α expression levels.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death
There is a strong association between Vascular endothelial growth factor (VEGF) immunostaining and angiographic vascularity[3], and VEGF over-expression in tumor cells is directly correlated with tumor angiogenesis in HCC4
We found that the expression levels of Krüppel-like factor 8 (KLF8) and VEGFA were highly correlated in hepatocellular carcinoma (HCC) tissue samples, and KLF8 up-regulation induced VEGFA expression in HCC cell lines
Summary
Received: 20 March 2018 Accepted: 3 October 2018 Published: xx xx xxxx carcinoma. Sanuo Cheng[1,2], Xingping Zhang[1], Yali Xu3, Xiaobo Dai[1], Jiachu Li1, Tao Zhang1 & Xiaopin Chen[1]. Tumor angiogenesis plays a critical role in hepatocellular carcinoma (HCC) development and progression, but its mechanism is unclear. Our results indicate that KLF8 may induce angiogenesis in HCC by binding to the CACCC region of the VEGFA promoter to induce VEGFA promoter activity and through FAK to activate PI3K/AKT signaling to regulate HIF-1α expression levels. KLF8 is a member of the Krüppel-like C2H2 zinc-finger transcription factor family of proteins[9], KLF8 induces tumor cell epithelial-to-mesenchymal transition (EMT), maintains the invasive potential of cancer, and plays a crucial role in the metastatic progression of human carcinoma[10,11,12]. KLF8 might activate the PI3K/ AKT signal pathway through FAK to increase P-PDK1(Ser241) levels and P-AKT(Thr308) or P-AKT(Ser473) and HIF-1α levels to induce VEGFA protein expression
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