Oncotarget

Research Papers:

VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma

Zhen-Chuan Liu, Kuo Cao, Zhao-Hua Xiao, Liang Qiao, Xue-Qing Wang, Bin Shang, Yang Jia and Zhou Wang _

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Oncotarget. 2017; 8:65642-65658. https://doi.org/10.18632/oncotarget.20020

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Abstract

Zhen-Chuan Liu1, Kuo Cao1, Zhao-Hua Xiao1, Liang Qiao1, Xue-Qing Wang1, Bin Shang1, Yang Jia1 and Zhou Wang1

1Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

Correspondence to:

Zhou Wang, email: wangzhou1962@hotmail.com

Keywords: esophageal squamous cell carcinoma, vaccinia-related kinase 1, cisplatin, c-Jun, c-MYC

Received: June 08, 2017     Accepted: July 25, 2017     Published: August 07, 2017

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) is a common malignant disease characterized by poor prognosis. Chemoresistance remains a major cause of ESCC relapse. Vaccinia-related kinase 1 (VRK1) has previously been identified as a cancer-related gene. However, there is little research demonstrating an association between VRK1 and ESCC. In this study, we show that VRK1 is overexpressed in ESCC primary tumor samples and cell lines. VRK1 expression was significantly correlated with clinical characteristics and predicted poor outcomes in ESCC patients. Functionally, knockdown of VRK1 inhibited ESCC cell proliferation, survival, migration and invasion; conversely, VRK1 overexpression produced the opposite effects. Furthermore, we found that up-regulation of VRK1 promoted cisplatin (CDDP) resistance in ESCC both in vitro and in vivo, whereas knockdown of VRK1 reduced this resistance. Further studies verified that VRK1 phosphorylated c-Jun and that the VRK1/c-Jun pathway contributed to CDDP resistance in ESCC. Mechanistically, a dual luciferase reporter assay revealed that c-Jun transcriptionally activated the expression of c-MYC. Silencing c-MYC abolished the c-Jun-mediated CDDP resistance of ESCC cells. A Kaplan-Meier analysis indicated that c-MYC is a potential prognostic factor in ESCC. Finally, luteolin, a VRK1 inhibitor, attenuated the malignant biological behaviors and CDDP resistance in ESCC cells. Collectively, we conclude that VRK1 promotes CDDP resistance through c-MYC by activating c-Jun and potentiating a malignant phenotype in ESCC. Our studies provide novel insight into the role of VRK1 in carcinogenesis and indicate that VRK1 can serve as a potential therapeutic target in ESCC.


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