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RNF19A inhibits bladder cancer progression by regulating ILK ubiquitination and inactivating the AKT/mTOR signalling
Hao Deng1,2, Guanghai Ji1, Jun Ma3
1Department of Urology, The First Affiliated Hospital of Yangtze University, The First people's Hospital of Jingzhou, Jingzhou, 434000, China.
Background:
The role of the RING finger protein superfamily in carcinogenesis has been widely studied, but one member of this family, RNF19A, has not yet been thoroughly explored in bladder cancer (BCa).
Methods:
The expression levels of RNF19A in BCa samples and cell lines were analysed through data mining of public resources and further experiments. BCa cells in which RNF19A was stably overexpressed or knocked down were generated through lentivirus infection. The effects of RNF19A on cell proliferation, migration, and invasion were explored by performing a series of in vitro experiments, including CCK-8, colony formation, wound healing, and Transwell invasion assays. Using bioinformatics methods and multiple experiments, including western blot, qRT‒PCR, immunoprecipitation, cycloheximide, ubiquitination, and rescue assays, the mechanism underlying the effect of RNF19A on the progression of BCa was investigated.
Results:
Here, we found that RNF19A expression was reduced in BCa samples and cell lines and that lower RNF19A expression predicted shorter overall survival of BCa patients. Functionally, forced expression of RNF19A suppressed BCa cell proliferation, migration, and invasion by inactivating the AKT/mTOR signalling pathway, whereas silencing RNF19A had the opposite effects. Mechanistically, RNF19A could directly interact with ILK and promote its ubiquitination and degradation. Rescue experiments revealed that forced ILK expression partially rescued the decreased phosphorylation of AKT, mTOR, and S6K1 caused by RNF19A overexpression and that the increased levels of the p-AKT, p-mTOR, and p-S6K1 proteins induced by RNF19A knockdown were eliminated after silencing ILK. Similarly, the effects of RNF19A overexpression or knockdown on the phenotypes of cell proliferation, migration, and invasion could also be restored by forced or decreased ILK expression.
Conclusions:
RNF19A suppressed the proliferation, migration, and invasion abilities of BCa cells by regulating ILK ubiquitination and inactivating the AKT/mTOR signalling pathway. RNF19A might be a potential prognostic biomarker and promising therapeutic target for BCa.
Insights
RNF19A, a RING finger protein, suppresses bladder cancer progression by inhibiting cell proliferation, migration, and invasion. It targets ILK for degradation, inactivating the AKT/mTOR pathway, suggesting its potential as a prognostic biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The RING finger protein superfamily's role in cancer is known, but RNF19A's specific involvement in bladder cancer (BCa) remains under-explored.
- RNF19A, a member of the RING finger protein superfamily, has not been extensively studied in the context of bladder cancer (BCa).
Purpose of the Study:
- To investigate the expression and function of RNF19A in bladder cancer (BCa).
- To elucidate the underlying molecular mechanisms by which RNF19A influences BCa progression.
- To evaluate RNF19A as a potential prognostic biomarker and therapeutic target for BCa.
Main Methods:
- Expression analysis of RNF19A in BCa tissues and cell lines using public data and experimental validation.
- In vitro functional assays (proliferation, migration, invasion) in BCa cells with altered RNF19A levels.
- Mechanistic studies involving bioinformatics, western blot, qRT-PCR, co-immunoprecipitation, ubiquitination assays, and rescue experiments to explore RNF19A's interaction with ILK and the AKT/mTOR pathway.
Main Results:
- RNF19A expression is downregulated in BCa, and low expression correlates with poorer patient survival.
- Overexpression of RNF19A suppresses BCa cell proliferation, migration, and invasion, while RNF19A knockdown enhances these processes.
- RNF19A directly interacts with ILK, promoting its ubiquitination and degradation, leading to the inactivation of the AKT/mTOR signaling pathway.
Conclusions:
- RNF19A acts as a tumor suppressor in BCa by inhibiting cell proliferation, migration, and invasion through ILK ubiquitination and subsequent AKT/mTOR pathway inactivation.
- RNF19A demonstrates potential as a prognostic biomarker and a promising therapeutic target for bladder cancer.
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