Huang Maowen, Hua Xiaohui, Xu Jiheng, Tian Zhongxian, Wang Jiajing, Chen Hengchao, Wang Xuyao, Shu Peng, Ye Hongyan, Shu Jianfeng, Huang Chuanshu
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Clinical Laboratory, Beilun People's Hospital, Zhejiang, China.
Cell Cycle. 2022 May 15:1-14. doi: 10.1080/15384101.2022.2074623.
Bladder cancer (BC) is the most expensive cancer to manage on a per-patient basis, costing about $4 billion in total healthcare expenditure per annum in America alone. Therefore, identifying a natural compound for prevention of BC is of tremendous importance for managing this disease. Previous studies have identified isorhapontigenin (ISO) as having an 85% preventive effect against invasive BC formation induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). The results showed here that ISO treatment inhibited EGF-induced cell transformation of human urothelial cells through induction of tumor suppressor p27 transcription secondary to activation of an E2F1-dependentpathway.ISOtreatmentrenderedcellsresistanttoEGF-induced anchorage-independent growth concurrent with p27 protein induction in both UROtsa and SV-HUC-1 cells. ISO inhibition of EGF-induced cell transformation could be completely reversed by knockdown of p27, indicating that this protein was essential for the noted ISO inhibitory action. Mechanistic studies revealed that ISO treatment resulted in increased expression of E2F1, which in turn bound to its binding site in p27 promoter and initiated p27 transcription. The E2F1 induction was due to the elevation of its translation caused by ISO-induced miR-205 downregulation. Consistently, miR-205 was found to be overexpressed in human BCs, and ectopic expression of miR-205 mitigated ISO inhibitory effects against EGF-induced outcomes. Collectively, the results here demonstrate that ISO exhibits its preventive effect on EGF-induced human urothelial cell transformation by induction of p27 through a miR-205/E2F1 axis. This is distinct from what has been described for the therapeutic effects of ISO on human BC cells.
膀胱癌（BC）是按每位患者计算管理成本最高的癌症，仅在美国每年的医疗总支出就约为40亿美元。因此，确定一种预防膀胱癌的天然化合物对于控制这种疾病极为重要。先前的研究已确定异去甲淫羊藿素（ISO）对由N-丁基-N-（4-羟基丁基）亚硝胺（BBN）诱导的侵袭性膀胱癌形成具有85%的预防作用。此处的结果表明，ISO处理通过激活E2F1依赖性途径诱导肿瘤抑制因子p27转录，从而抑制表皮生长因子（EGF）诱导的人尿道上皮细胞转化。在UROtsa和SV-HUC-1细胞中，ISO处理使细胞对EGF诱导的不依赖贴壁生长产生抗性，同时诱导p27蛋白。敲低p27可完全逆转ISO对EGF诱导的细胞转化的抑制作用，表明该蛋白对于ISO的上述抑制作用至关重要。机制研究表明，ISO处理导致E2F1表达增加，E2F1进而与其在p27启动子中的结合位点结合并启动p27转录。E2F1的诱导是由于ISO诱导的miR-205下调导致其翻译水平升高。一致的是，发现miR-205在人膀胱癌中过表达，异位表达miR-205可减轻ISO对EGF诱导的结果的抑制作用。总体而言，此处的结果表明，ISO通过miR-205/E2F1轴诱导p27，从而对EGF诱导的人尿道上皮细胞转化发挥预防作用。这与ISO对人膀胱癌细胞的治疗作用不同。
