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Forkhead Box R2 Knockdown Decreases Chemoresistance to Cisplatin via MYC Pathway in Bladder Cancer

Yangle Li, Xiongbing Zu, Xiheng Hu, Long Wang, Wei He

Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)

Med Sci Monit 2019; 25:8928-8939

DOI: 10.12659/MSM.917345

Available online:

Published: 2019-11-25

BACKGROUND: Bladder cancer is a very common urological cancer globally, and cisplatin- or gemcitabine-based chemotherapy is essential for advanced bladder cancer patients. Many patients with bladder cancer have a relatively poor response to chemotherapy, leading to failure of clinical treatment. We mined the GSE77883 GEO dataset, identifying FoxR2 as being a significantly upregulated gene in T24 chemoresistant cells. Herein, we assessed how FoxR2 functions in bladder cancer cell chemoresistance.
MATERIAL AND METHODS: Cisplatin-resistant T24 (T24/DDP) cells were constructed by administering increasing concentrations of cisplatin, and differences in expression of FoxR2 were examined in T24/DDP and T24 cells. FoxR2 loss- and gain-of-function cells models were established in T24/DDP and T24 cells, respectively. Cell survival, clone formation, cell cycle, and cell apoptosis were assessed, and the MYC pathway was verified.
RESULTS: FoxR2 was significantly upregulated in T24/DDP cells compared to T24 cells. Knockdown of FoxR2 in T24/DDP cells, survival rate, and clone formation were decreased, G1/S phase transition was suppressed, and cell apoptosis was promoted. These results were reversed by restoration of FoxR2 levels in T24 cells. We found that FoxR2 knockdown enhanced sensitivity to cisplatin, whereas MYC overexpression antagonized chemosensitivity in T24/DDP cells.
CONCLUSIONS: FoxR2 knockdown decreases chemoresistance to cisplatin via the MYC pathway in bladder cancer cells, and this may be a target for overcoming chemoresistance in bladder cancer.

Keywords: Cisplatin, Drug Resistance, Forkhead Transcription Factors, Urinary Bladder Neoplasms