Liu Zhiqi, Liu Jie, Zhao Li, Geng Hao, Ma Jiaxing, Zhang Zhiqiang, Yu Dexin, Zhong Caiyun
Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China.
Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Int J Oncol. 2017 Apr;50(4):1321-1329. doi: 10.3892/ijo.2017.3887. Epub 2017 Feb 21.
Overexposure to benzidine has been manifested as an important cause of bladder cancer. However, the molecular mechanism of benzidine-induced malignancy is still insufficiently interpreted. Epithelial-mesenchymal transition (EMT) is a crucial pathophysiological process in embryonic development as well as initiation and development of epithelium-originated malignant tumors. The role of extracellular regulated protein kinase 5 (ERK5) in benzidine-meditated bladder cancer development has not been explored. In the present study, we explored the role of ERK5/AP-1 pathway in benzidine-induced EMT in human normal urothelial cells and the intervention effect of curcumin on bezidine-induced EMT. We found that benzidine-induced EMT in SV-40 immortalized human urothelial cells (SV-HUC-1) at low concentrations. We detected that ERK5/AP-1 pathway was notably activated. Specific ERK5 inhibitor, XMD8-92 was applied to determine the role of ERK5 in benzidine-induced EMT. Results indicated that XMD8-92 reversed the EMT process. Furthermore, curcumin effectively attenuated benzidine-induced urocystic EMT by suppressing ERK5/AP-1 pathway. In conclusion, the present study revealed the positive role of ERK5/AP-1 in benzidine-provoked urocystic EMT and the curcumin promising use in bladder cancer prevention and intervention via ERK5/AP-1 pathway.
长期接触联苯胺已被证明是膀胱癌的一个重要病因。然而，联苯胺诱发恶性肿瘤的分子机制仍未得到充分阐释。上皮-间质转化（EMT）是胚胎发育以及上皮源性恶性肿瘤发生和发展过程中的一个关键病理生理过程。细胞外调节蛋白激酶5（ERK5）在联苯胺介导的膀胱癌发展中的作用尚未得到研究。在本研究中，我们探讨了ERK5/AP-1信号通路在联苯胺诱导人正常尿路上皮细胞发生EMT过程中的作用以及姜黄素对联苯胺诱导的EMT的干预作用。我们发现低浓度的联苯胺可诱导SV-40永生化人尿路上皮细胞（SV-HUC-1）发生EMT。我们检测到ERK5/AP-1信号通路被显著激活。应用特异性ERK5抑制剂XMD8-92来确定ERK5在联苯胺诱导的EMT中的作用。结果表明，XMD8-92可逆转EMT过程。此外，姜黄素通过抑制ERK5/AP-1信号通路有效减轻了联苯胺诱导的膀胱上皮EMT。总之，本研究揭示了ERK5/AP-1在联苯胺诱发的膀胱上皮EMT中的积极作用，以及姜黄素通过ERK5/AP-1信号通路在膀胱癌预防和干预方面具有潜在应用价值。
