PBK overexpression promotes metastasis of hepatocellular carcinoma via activating ETV4-uPAR signaling pathway

尿激酶受体 癌症研究 染色质免疫沉淀 基因敲除 转移 生物 信号转导 下调和上调 肝细胞癌 癌症 发起人 细胞生物学 受体 细胞培养 基因表达 基因 遗传学 生物化学
作者
Qiuxia Yang,Shan Zhong,Lin He,Xiaojiong Jia,Hua Tang,Sheng‐Tao Cheng,Ji‐Hua Ren,Haibo Yu,Li Zhou,Hongzhong Zhou,Fang Ren,Zhongwen Hu,Rui Gong,Ailong Huang,Juan Chen
出处
期刊:Cancer Letters [Elsevier BV]
卷期号:452: 90-102 被引量:80
标识
DOI:10.1016/j.canlet.2019.03.028
摘要

Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.
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