Transcribed ultraconserved region Uc.63+ promotes resistance to cisplatin through regulation of androgen receptor signaling in bladder cancer

Abstract

Cisplatin (CDDP)-based combination chemotherapy is the standard for muscle-invasive bladder cancer (MIBC). However, nearly all patients undergoing CDDP chemotherapy become refractory due to the development of CDDP resistance. Therefore, clarification of the mechanisms of CDDP resistance is urgently needed. The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are highly conserved across species and are associated with carcinogenesis and cancer progression. In addition, emerging evidence has shown the involvement of androgen receptor (AR) signals in urothelial carcinoma (UC) progression. The aim of the present study was to investigate the expression of transcribed ultraconserved region Uc.63+, and to analyze the effects of Uc.63+ on AR expression and CDDP resistance in UC. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that the expression of Uc.63+ was higher in UC tissues than that in non-neoplastic bladder tissues and 15 types of normal tissue. An MTT assay revealed that Uc.63+ was involved in cell proliferation. Western blotting demonstrated that the expression of AR was disrupted by the overexpression or knockdown of Uc.63+ in AR-positive UMUC3 cells. Furthermore, knockdown of Uc.63+ increased sensitivity to CDDP in UMUC3 cells. Conversely, overexpression of Uc.63+ had no effect on CDDP sensitivity in AR-negative RT112 cells. Additionally, we observed that the expression of Uc.63+ was increased in CDDP-resistant UMUC3 cells (UMUC3-CR) in comparison with that in parental UMUC3 cells. Knockdown of Uc.63+ re-sensitized the UMUC3-CR cells to CDDP. These results indicated that Uc.63+ may be a promising therapeutic target to overcome CDDP resistance in UC.