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Published on: October 30, 2013
Suppression of cisplatin induced ATF3 expression and apoptosis by BK polyomavirus and its encoded microRNA in bladder
Yi-Jung Li1, Yu-Hsuan Chen2, Jiun-Wen Wang2
1Kidney Research Center and Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Abstract:
Recent evidence links BK polyomavirus (BKPyV) infection to an increased risk of bladder cancer. This study investigates the role of BKPyV and its microRNA, miR-B1, in cisplatin-induced apoptosis. PCR analysis detected BKPyV DNA in 3 of 22 urothelial carcinoma (UC) samples from a non-transplant population. Bladder cancer cells infected with BKPyV showed increased proliferation and miR-B1-3p and -5p expression. Bioinformatics analysis identified a miR-B1-5p target site in the 3'-UTR of activating transcription factor 3 (ATF3), confirmed by a luciferase assay. The inhibitory effect was further validated by reduced ATF3 mRNA levels following overexpression of miR-B1 vectors or 5p mimics. Cisplatin treatment upregulated ATF3 expression, as shown by qPCR and immunoblotting. Overexpression of ATF3 mitigated the cisplatin-induced reduction in cell viability and elevated apoptotic markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). BKPyV infection or large T antigen (TAg) overexpression suppressed cisplatin-induced ATF3 expression, reducing its cytotoxicity and apoptotic marker expression. However, overexpression of ATF3 in BKPyV-infected bladder cancer cells attenuated BKPyV's inhibitory effects, restoring cisplatin-induced cytotoxicity and apoptotic marker expression, suggesting BKPyV infection promotes resistance to cisplatin cytotoxicity. Transfection with miR-B1 vectors or miR-B1-5p mimics decreased cisplatin-induced annexin V-positive cells, caspase-3 activity, and apoptotic marker expression, indicating that miR-B1 suppresses cisplatin-induced apoptosis. In conclusion, this study demonstrates that BKPyV promotes bladder cancer cell growth and impairs cisplatin-induced apoptosis, with miR-B1 targeting ATF3 as a key mechanism. Targeting BKPyV replication or regulating miR-B1 expression could offer potential therapeutic strategies for managing BKPyV-positive and cisplatin-resistant urothelial carcinoma.
Insights
BK polyomavirus (BKPyV) promotes bladder cancer growth and resistance to cisplatin by inhibiting apoptosis via its microRNA, miR-B1, which targets ATF3. This suggests new therapeutic strategies for urothelial carcinoma.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- BK polyomavirus (BKPyV) infection is linked to increased bladder cancer risk.
- Understanding BKPyV's role in urothelial carcinoma (UC) pathogenesis and treatment resistance is crucial.
Purpose of the Study:
- To investigate the role of BKPyV and its microRNA, miR-B1, in cisplatin-induced apoptosis in bladder cancer.
- To elucidate the molecular mechanisms underlying BKPyV-mediated chemoresistance.
Main Methods:
- PCR detection of BKPyV DNA in UC samples.
- Cell culture experiments involving BKPyV infection, gene/microRNA overexpression, and cisplatin treatment.
- Bioinformatics analysis, luciferase assays, qPCR, and immunoblotting to assess gene expression and protein levels.
- Apoptosis assays (annexin V staining, caspase-3 activity).
Main Results:
- BKPyV DNA detected in UC samples; BKPyV infection increased bladder cancer cell proliferation and miR-B1 expression.
- miR-B1-5p targets and downregulates activating transcription factor 3 (ATF3).
- BKPyV infection or TAg overexpression suppressed cisplatin-induced ATF3 upregulation, conferring resistance to cisplatin-induced apoptosis.
- miR-B1 overexpression mimicked this resistance by suppressing cisplatin-induced apoptosis.
Conclusions:
- BKPyV promotes bladder cancer cell growth and confers resistance to cisplatin by impairing apoptosis through the miR-B1/ATF3 axis.
- Targeting BKPyV replication or modulating miR-B1 expression may offer therapeutic avenues for BKPyV-positive, cisplatin-resistant urothelial carcinoma.
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02:23Abnormal Proliferation