Guo Changcheng, Kadier Aimaitiaji, Zhang Zhijin, Mao Shiyu, Yang Bin, Zheng Junhua, Yao Xudong
Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, Shanghai, 200072, China.
Cell Biol Toxicol. 2025 Jun 19;41(1):107. doi: 10.1007/s10565-025-10046-2.
Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients' survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression.
早期研究表明，使用抗雄激素恩杂鲁胺（Enz）进行雄激素剥夺治疗可使前列腺癌患者的生存期平均延长4.8个月。然而，Enz也可能通过增加前列腺癌（PCa）细胞侵袭而产生一些不良反应。在此我们发现，Enz治疗可增加SALL4表达，从而增加癌干细胞样（CSC样）细胞群，进而导致PCa细胞侵袭增加。机制剖析显示，Enz可通过雄激素受体（AR）发挥作用，通过直接结合SALL4的5'-启动子来转录调控SALL4表达。这种Enz/AR/SALL4轴的结果可上调SOX2-OCT4表达，以增加CSC样细胞群和PCa细胞侵袭。总之，多个体外和体内实验的结果均表明，Enz可能通过改变AR/SALL4/SOX2-OCT4信号传导来增加CSC样细胞群，从而诱导PCa细胞侵袭增加的不良反应，而靶向SALL4可能会减少这种不良反应，进而进一步抑制PCa进展。
