Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer

Chia Sing Lu, Gia Shing Shieh, Chung Teng Wang, Bing Hua Su, Yu Chu Su, Yi Cheng Chen, Wu Chou Su, Pensee Wu, Wen Horng Yang, Ai Li Shiau, Chao Liang Wu

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)30844-30858
Number of pages15
JournalOncotarget
Volume8
Issue number19
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

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Keywords

  • All-trans retinoic acid
  • Bladder cancer
  • Drug resistance
  • Oct4
  • Tumor recurrence

ASJC Scopus subject areas

  • Oncology

Cite this

Lu, C. S., Shieh, G. S., Wang, C. T., Su, B. H., Su, Y. C., Chen, Y. C., Su, W. C., Wu, P., Yang, W. H., Shiau, A. L., & Wu, C. L. (2017). Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer. Oncotarget, 8(19), 30844-30858. https://doi.org/10.18632/oncotarget.9602