VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma
| Autor: | Zhen Chuan Liu, Xue Qing Wang, Bin Shang, Yang Jia, Zhao Hua Xiao, Zhou Wang, Kuo Cao, Liang Qiao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
cisplatin vaccinia-related kinase 1 Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine medicine Gene silencing neoplasms Cisplatin Gene knockdown Kinase Cell growth c-jun c-Jun digestive system diseases esophageal squamous cell carcinoma 030104 developmental biology c-MYC Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Carcinogenesis medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Zhen-Chuan Liu 1 , Kuo Cao 1 , Zhao-Hua Xiao 1 , Liang Qiao 1 , Xue-Qing Wang 1 , Bin Shang 1 , Yang Jia 1 and Zhou Wang 1 1 Department 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. |
| Databáze: | OpenAIRE |
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