Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer
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Chia-Sing Lu1,*, Gia-Shing Shieh2,*, Chung-Teng Wang1,*, Bing-Hua Su3, Yu-Chu Su1, Yi-Cheng Chen1, Wu-Chou Su4, Pensee Wu5, Wen-Horng Yang6, Ai-Li Shiau1,7, Chao-Liang Wu1,3
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan
3Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5Institute for Science & Technology in Medicine, Keele University, Keele, United Kingdom
6Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
7Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
*These authors have contributed equally to this work
Chao-Liang Wu, email: email@example.com
Ai-Li Shiau, email: firstname.lastname@example.org
Keywords: Oct4, drug resistance, tumor recurrence, bladder cancer, all-trans retinoic acid
Received: May 17, 2015 Accepted: April 23, 2016 Published: May 26, 2016
Cancer cells initially characterized as sensitive to chemotherapy may acquire resistance to chemotherapy and lead to tumor recurrence through the expansion of drug-resistant population. Acquisition of drug resistance to conventional chemotherapy is a major obstacle in the treatment of recurrent cancer. Here we investigated whether anticancer drugs induced Oct4 expression, thereby contributing to acquired drug resistance and tumor recurrence in bladder cancer. We identified a positive correlation of Oct4 expression with tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma (TCC). Increased Oct4 levels in bladder tumors were associated with short recurrence-free intervals in the patients. Chemotherapy induced Oct4 expression in bladder cancer cells. Notably, treatment with cisplatin increased CD44-positive bladder cancer cells expressing Oct4, representing cancer stem-like cell subpopulation. Forced expression of Oct4 reduced, whereas knockdown of Oct4 enhanced, drug sensitivity in bladder cancer cells. Furthermore, tumor cells overexpressing Oct4 responded poorly to cisplatin in vivo. In regard to clinical relevance, inhibition of Oct4 by all-trans retinoic acid (ATRA) synergistically increased sensitivity to cisplatin in bladder cancer cells. Furthermore, the combination of cisplatin and ATRA was superior to cisplatin alone in suppressing tumor growth. Therefore, our results provide evidence that Oct4 increases drug resistance and implicate that inhibition of Oct4 may be a therapeutic strategy to circumvent drug resistance.
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