WWOX Modulates ROS-Dependent Senescence in Bladder Cancer
Ching-Wen Liu1, Po-Hen Chen2, Tsan-Jung Yu3
1Department of Senior Citizen Health Service and Management, Yuh-Ing Junior College of Health Care and Management, Kaohsiung 80776, Taiwan.
Abstract:
The tumor-suppressor gene, WW domain-containing oxidoreductase (WWOX), has been found to be lost in various types of cancers. ROS result as a tightly regulated signaling process for the induction of cell senescence. The aim of this study was to investigate the role of WWOX in the regulation of ROS and cell senescence, which is intriguing in terms of the possible mechanism of WWOX contributing to bladder cancer. In this study, we used the AY-27 rat bladder tumor cell line and F344 orthotopic bladder tumor models to reveal the pro-senescence effects of WWOX and the corresponding underlying mechanism in bladder cancer. WWOX-overexpressing lentivirus (LV-WWOX) remarkably stimulated cellular senescence, including increased senescence-associated secretory phenotype (SASP) formation, enlarged cellular morphology, and induced SA-β-Gal-positive staining. A further mechanism study revealed that the pro-senescence effect of LV-WWOX was dependent on increased intercellular reactive oxygen species (ROS) generation, which subsequently triggered p21/p27. Moreover, LV-WWOX significantly inhibited the tumor size by 30.49% in the F344/AY-27 rat orthotopic model (p < 0.05) by activating cellular senescence. The expression of p21 was significantly enhanced in the orthotopic bladder tumors under WWOX treatment. The orthotopic bladder tumors in the groups of rats verified the effect in vivo. Our study suggests that WWOX, an ROS-dependent senescence-induced gene, could be further studied for its therapeutic implications in bladder cancer.
Insights
The WW domain-containing oxidoreductase (WWOX) gene promotes bladder cancer cell senescence by increasing reactive oxygen species (ROS). WWOX inhibits tumor growth, suggesting therapeutic potential for bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Senescence
Background:
- WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene frequently lost in cancers.
- Reactive oxygen species (ROS) are critical signaling molecules in inducing cell senescence.
Purpose of the Study:
- To investigate the role of WWOX in regulating ROS and cell senescence.
- To explore the mechanism of WWOX in bladder cancer progression.
Main Methods:
- Utilized AY-27 rat bladder tumor cell line and F344 orthotopic bladder tumor models.
- Employed WWOX-overexpressing lentivirus (LV-WWOX) to assess senescence induction.
- Analyzed senescence markers, ROS generation, and cell cycle regulators (p21/p27).
Main Results:
- LV-WWOX significantly induced cellular senescence, including SASP formation, enlarged morphology, and SA-β-Gal staining.
- WWOX-induced senescence was dependent on increased ROS generation, activating p21/p27.
- LV-WWOX inhibited tumor size by 30.49% in vivo by activating cellular senescence and enhancing p21 expression.
Conclusions:
- WWOX acts as a pro-senescence gene in bladder cancer through ROS induction.
- WWOX demonstrates therapeutic potential for bladder cancer by inhibiting tumor growth.
- Further research into WWOX's therapeutic implications in bladder cancer is warranted.
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