JNK2 downregulation promotes tumorigenesis and chemoresistance by decreasing p53 stability in bladder cancer
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Chun-Wu Pan1,*, Hailong Liu1,*, Yu Zhao2, Chenchen Qian3, Liguo Wang4, Jun Qi1
1Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Huangpu, Shanghai 200092, China
2Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, US
3Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
4Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, US
*These authors have contributed equally to this work
Jun Qi, e-mail: [email protected]
Chun-Wu Pan, e-mail: [email protected]
Keywords: JNK2, p53, bladder cancer, tumorigenesis, chemoresistance
Received: February 07, 2016 Accepted: April 16, 2016 Published: April 27, 2016
Bladder cancer is one of the most common malignancies of the urinary system, and the 5-year survival rate remains low. A comprehensive understanding of the carcinogenesis and progression of bladder cancer is urgently needed to advance treatment. c-Jun N-terminal kinase-2 (JNK2) exhibits both tumor promoter and tumor suppressor actions, depending on tumor type. Here, we analyzed the JNK2 function in bladder cancer. Using gene expression microarrays, we demonstrated that JNK2 mRNA is downregulated in an orthotopic rat model of bladder cancer. JNK2 protein levels were lower in rat and human bladder cancer tissues than in normal tissues, and the levels correlated with those of p53. Moreover, JNK2 phosphorylated p53 at Thr-81, thus protecting p53 from MDM2-induced proteasome degradation. Decreased expression of JNK2 in T24 cells conferred resistance to cell death induced by mitomycin C. Furthermore, lower JNK2 expression was associated with poorer overall survival among patients who underwent radical cystectomy. These results indicate that JNK2 acts as a tumor suppressor in bladder cancer, and that decreased JNK2 expression promotes bladder cancer tumorigenesis.
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