Study on the role of chemotherapeutics-induced Octamer-binding transcription factor 4 (Oct4) expression in drug resistance and tumor recurrence in bladder cancer

  • 盧 佳杏

Student thesis: Doctoral Thesis


Acquisition of drug resistance to conventional chemotherapy is a challenge in treating recurrent cancer Bladder cancer has the highest recurrence rate of any malignancy Although primary tumors can be eliminated by surgery chemotherapy and radiotherapy the tumors recur frequently and progress to muscle-invasive disease Here we investigated whether anticancer drugs induced Oct4 expression and ultimately results in tumor recurrence in bladder cancer We identified a positive correlation of the expression levels of Oct4 with the rate of tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma 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 Overexpression of Oct4 reduced whereas knockdown of Oct4 enhanced drug sensitivity in bladder cancer cells Furthermore there was a poor response to cisplatin treatment in vivo when tumor cells overexpressed Oct4 In terms of clinical relevance inhibition of Oct4 by all-trans retinoic acid synergistically increased sensitivity to cisplatin in bladder cancer cells Furthermore the combination of cisplatin and all-trans retinoic acid was superior to cisplatin alone in suppressing tumor growth At last Luciferase reporter and chromatin immunoprecipitation (ChIP) assays demonstrated that Oct4 could transactivate the MDR1 promoter by binding to the Oct4 response element These results indicated Oct4 involved in chemodrugs efflux Patients with Oct4 and/or MDR1 high-expressing tumors were associated with shorter recurrence-free intervals compared with patients with Oct4 and/or MDR1 low-expressing tumors Therefore our findings provide evidence that Oct4 can mediate acquired drug resistance to anticancer drugs and implicate that targeting Oct4 may be a therapeutic strategy to circumvent drug resistance
Date of Award2016 Aug 1
Original languageEnglish
SupervisorChao-Liang Wu (Supervisor)

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