Journal
CANCER LETTERS
Volume 452, Issue -, Pages 90-102Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.03.028
Keywords
HCC; PDZ-Binding kinase; Metastasis; ETV4; uPAR
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Funding
- National Natural Science Foundation of China [81672012,81871656, 8181101099]
- Chongqing Natural Science Foundation [cstc2016jcyjA0183, cstc2018jcyjAX0114]
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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 im-munoprecipitation (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 m 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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