Abstract
Urinary bladder cancer (UBC) is largely caused by exposure to toxic chemicals including those in cigarette smoke (i.e. BBN). An activating SNP in RGS6 is associated with a pronounced reduction in UBC risk, especially among smokers. However, the mechanism underlying this reduction remains unknown. Here we demonstrate that RGS6 is robustly expressed in human urothelium, where urothelial cell carcinoma originates, and is downregulated in human UBC. Utilizing RGS6−/− mice we interrogated a possible role for RGS6 as a tumor suppressor using the BBN-induced bladder carcinogenesis model that closely recapitulates human disease. As in humans, RGS6 is robustly expressed in mouse urothelium. RGS6 loss dramatically accelerates BBN-induced bladder carcinogenesis, with RGS6−/− mice consistently displaying more advanced pathological lesions than RGS6+/+ mice. Furthermore, BBN treatment promotes urothelial RGS6 mRNA and protein downregulation. RGS6 loss impairs p53 activation and promotes aberrant accumulation of oncogenic protein DNMT1 in urothelium. Tumor suppressor RASSF1A, a DNMT1-regulated gene, is also silenced, likely via methylation of its promoter during BBN exposure. We hypothesize that this BBN-induced RGS6 loss represents a critical hit in UBC as it irrevocably impairs the anti-proliferative actions of the ATM/p53 and RASSF1A pathways. Consistent with these findings, RGS6−/− mice treated with CP-31398, a p53-stablizing agent, and/or 5-Aza, a DNMT1 inhibitor, are protected from BBN-induced tumorigenesis. Together, our data identify RGS6 as a master tumor suppressor modulating two critical signaling pathways that are often dysregulated in UBC; therefore, RGS6 represents a potential novel biomarker for UBC diagnosis/prognosis and an appealing new target in its treatment.
Highlights
Urinary bladder cancer (UBC), the fifth most common cancer in the U.S, is one of the deadliest malignancies worldwide [1]
Given that an activating SNP in the human RGS6 gene is associated with a reduced risk of bladder cancer [20], we examined the possibility that RGS6 functions as a tumor suppressor by examining its expression in UBC
These findings demonstrate that RGS6, a protein previously linked to reduced UBC risk, is highly expressed in the urothelium where approximately 90% of UBCs arise and that RGS6-/- mice can be employed to study its tumor suppressor role in bladder
Summary
Urinary bladder cancer (UBC), the fifth most common cancer in the U.S, is one of the deadliest malignancies worldwide [1]. More than 90% of UBCs are urothelial cell carcinomas ( known as transitional cell carcinoma) [5], which can be classified into non-invasive and invasive subtypes, with the latter posing greater risk of metastases and lethality [6]. Studies in both human bladder tumor specimens and mouse models have implicated multiple signaling pathways in UBC carcinogenesis and progression [7]. Our understanding of the pathogenic mechanisms underlying UBC initiation and progression remains insufficient and represents a critical barrier to UBC detection and treatment
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