長鏈非編碼核糖核酸藉由調控微小核糖核酸-31影響上泌尿道上皮癌細胞對順鉑和吉西他濱的抗藥能力
徐偉齊¹、李威明^{2, 3, 4}、黃阿梅^{1, 5, 6}、張玲麗^{1, 7}、林慧惠^{1, 2}、吳文正^{1, 2, 3}、李經家^{2, 3}、柯宏龍^{1, 2, 3}*

高雄醫學大學 醫學院醫學研究所 ¹，泌尿學科 ²，高雄醫學大學附設醫院 泌尿部 ³ ;
衛生福利部屏東醫院泌尿科 ⁴ ; 高雄醫學大學 醫學院臨床醫學研究所 ⁵，
醫學研究所 生物化學科 ⁶，微生物與免疫學科 ⁷

Long non-coding RNA mediates cisplatin and gemcitabine resistance in upper tract urothelial carcinoma cells by sponging of miR-31
Wei-Chi Hsu ¹, Wei-Ming Li ^{2, 3, 4}, A-Mei Huang ^{1, 5, 6, 7}, Lin-Li Chang ^{1, 8}, Hui-Hui Lin ^{1, 2},
Wen-Jeng Wu ^{1, 2, 3}, Ching-Chia Li ^{2, 3}, Hung-Lung Ke ^{1, 2, 3} *

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ² Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ³ Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. ⁴ Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan. ⁵ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ⁶ Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. ⁷ Department of Microbiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Purpose:

Chemotherapy is suggested perioperatively for advanced upper tract urothelial carcinoma (UTUC) to improve recurrence-free and cancer-specific survivals. The standard regimens of chemotherapy are gemcitabine (GEM) and cisplatin (CDDP). After repeated chemotherapy, 30% of the patients will develop drug resistance and the disease will progress. Therefore, it is very important to clarify the mechanism of chemotherapy resistance and overcome it. This study aimed to investigate whether miR-31 can enhance the chemosensitivity of CDDP and GEM and the molecular mechanisms.

Material and Methods:

In this study, we established BFTC909 derived CDDP-resistant cells (BFTC909-CR) and GEM-resistant cells (BFTC909-GR). The effects of miR-31, CDDP and GEM on the chemosensitivity of cells were analyzed by WST-1. Western blot was applied to detect anti-apoptotic and multidrug resistant protein expression. Silencing of lncRNA was to examine CDDP and GEM response to UTUC cells and analyzing miR-31 levels by real-time PCR.

Results: 

We found that the levels of miR-31 was down-regulated in UTUC tissue samples and cell lines. Bcl-2 and MDR1 had higher expression in CDDP and GEM resistant cells than parent cells. The combination of miR-31 with CDDP or GEM significantly decreased the expression of Bcl-2 and MDR1 as compared with drug treatment alone. In addition, we found that one lncRNA may direct target to miR-31. LncRNA knockdown induced miR-31 levels in BFTC909 cells and indicated that lncRNA may negatively regulate the expression of miR-31. Importantly, lncRNA silencing increased drug sensitivity in CDDP and GEM resistant cells.

Conclusion: 

Taken together, our study indicated that lncRNA/miR-31 might modulate CDDP or GEM -resistance through regulating Bcl-2 and MDR1 in UTUC cells.