W Wang1,2, J Qiu3, P Qu2, H Chen5, J Lan5, H Chen5, L Li6, M Gu7. 1. Department of Urology, Jiangsu Provincial People's Hospital, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. 2. Department of Urology, Yancheng First People's Hospital, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224000, Jiangsu, China. 3. Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China. 4. Department of Haematology, Yancheng First People's Hospital, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224000, Jiangsu, China. 5. Department of Pathology, Yancheng First People's Hospital, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224000, Jiangsu, China. 6. Translational Medicine Center, Yancheng First People's Hospital, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224000, Jiangsu, China. 7. Department of Urology, Jiangsu Provincial People's Hospital, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. lancetgu@aliyun.com.
Abstract
BACKGROUND: The regulator of cullins-1 (ROC1) is an essential subunit in the cullin-RING ligase (CRL) protein complex and has been shown to be critical in bladder cancer cell survival and progression. This study aimed to explore the molecular mechanism of ROC1 action in the malignant progression of bladder cancer. METHODS: This study utilized ex vivo, in vitro, and in vivo nude mouse experiments to assess the underlying mechanisms of ROC1 in bladder cancer cells. The expression of the components of the sonic hedgehog (SHH) pathway was determined by western blot analysis. ROC1 expression in human tumors was evaluated by immunohistochemistry. RESULTS: ROC1 overexpression promoted the growth of bladder cancer cells, whereas knockdown of ROC1 expression had the opposite effect in bladder cancer cells. Mechanistically, ROC1 was able to target suppressor of fused homolog (SUFU) for ubiquitin-dependent degradation, allowing Gli2 release from the SUFU complex to activate the SHH pathway. Furthermore, knockdown of SUFU expression partially rescued the ROC1 knockdown-suppressed SHH activity as well as cancer cell growth inhibition. In ex vivo experiments, tissue microarray analysis of human bladder cancer specimens revealed a positive association of ROC1 expression with the SHH pathway activity. CONCLUSION: This study demonstrated that dysregulation of the ROC1-SUFU-GLI2 axis plays an important role in bladder cancer progression and that targeting ROC1 expression is warranted in further investigations as a novel strategy for the future control of bladder cancer.
BACKGROUND: The regulator of cullins-1 (ROC1) is an essential subunit in the cullin-RING ligase (CRL) protein complex and has been shown to be critical in bladder cancer cell survival and progression. This study aimed to explore the molecular mechanism of ROC1 action in the malignant progression of bladder cancer. METHODS: This study utilized ex vivo, in vitro, and in vivo nude mouse experiments to assess the underlying mechanisms of ROC1 in bladder cancer cells. The expression of the components of the sonic hedgehog (SHH) pathway was determined by western blot analysis. ROC1 expression in humantumors was evaluated by immunohistochemistry. RESULTS:ROC1 overexpression promoted the growth of bladder cancer cells, whereas knockdown of ROC1 expression had the opposite effect in bladder cancer cells. Mechanistically, ROC1 was able to target suppressor of fused homolog (SUFU) for ubiquitin-dependent degradation, allowing Gli2 release from the SUFU complex to activate the SHH pathway. Furthermore, knockdown of SUFU expression partially rescued the ROC1 knockdown-suppressed SHH activity as well as cancer cell growth inhibition. In ex vivo experiments, tissue microarray analysis of humanbladder cancer specimens revealed a positive association of ROC1 expression with the SHH pathway activity. CONCLUSION: This study demonstrated that dysregulation of the ROC1-SUFU-GLI2 axis plays an important role in bladder cancer progression and that targeting ROC1 expression is warranted in further investigations as a novel strategy for the future control of bladder cancer.
Entities:
Keywords:
Bladder cancer; Gli2; ROC1; SUFU; Sonic hedgehog signaling
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