Department of Senior Citizen Health Service and Management, Yuh-Ing Junior College of Health Care and Management, Kaohsiung 80776, Taiwan.
Department of Medical Research, E-Da Hospital, Kaohsiung 82445, Taiwan.
Molecules. 2022 Oct 31;27(21):7388. doi: 10.3390/molecules27217388.
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.
抑癌基因 WW 结构域包含氧化还原酶（WWOX）已在多种类型的癌症中发现丢失。ROS 作为诱导细胞衰老的严格调控信号过程的结果。本研究旨在探讨 WWOX 在 ROS 和细胞衰老调节中的作用，这对于 WWOX 促进膀胱癌的可能机制具有重要意义。在这项研究中，我们使用 AY-27 大鼠膀胱肿瘤细胞系和 F344 原位膀胱肿瘤模型，揭示了 WWOX 在膀胱癌中的促衰老作用及其相应的潜在机制。过表达 WWOX 的慢病毒（LV-WWOX）显著刺激了细胞衰老，包括增加衰老相关分泌表型（SASP）形成、增大细胞形态和诱导 SA-β-Gal 阳性染色。进一步的机制研究表明，LV-WWOX 的促衰老作用依赖于细胞间活性氧（ROS）生成的增加，进而触发 p21/p27。此外，LV-WWOX 通过激活细胞衰老，使 F344/AY-27 大鼠原位模型中的肿瘤大小显著减少 30.49%（p<0.05）。在 WWOX 处理下，原位膀胱肿瘤中的 p21 表达明显增强。大鼠原位膀胱肿瘤验证了体内的效果。我们的研究表明，作为一种 ROS 依赖性衰老诱导基因的 WWOX，可进一步研究其在膀胱癌中的治疗意义。
