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

Abstract

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.

• Authors: Qiu-Xia Yang, Shan Zhong, Lin He, Xiao-Jiong Jia, Hua Tang, Sheng-Tao Cheng, Ji-Hua Ren, Hai-Bo Yu, Li Zhou, Hong-Zhong Zhou, Fang Ren, Zhong-Wen Hu, Rui Gong, Ai-Long Huang, Juan Chen
• Journal: Cancer letters (Cancer Lett) Vol. 452 Pg. 90-102 (06 28 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30914208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• ETV4 protein, human
• MRC2 protein, human
• Mannose-Binding Lectins
• Membrane Glycoproteins
• Proto-Oncogene Proteins c-ets
• RNA, Small Interfering
• Receptors, Cell Surface
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Female
• Hep G2 Cells
• Humans
• Liver (cytology, pathology)
• Liver Neoplasms (genetics, pathology)
• Male
• Mannose-Binding Lectins (genetics)
• Membrane Glycoproteins (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (biosynthesis, metabolism)
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis (genetics)
• Prognosis
• Proto-Oncogene Proteins c-ets (genetics)
• RNA Interference
• RNA, Small Interfering (genetics)
• Receptors, Cell Surface (genetics)
• Signal Transduction (genetics)