Department of Pediatrics, The First Hospital of Jilin University, Changchun 130021, Jilin Province, PR China.
Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, PR China.
Life Sci. 2020 Oct 1;258:118154. doi: 10.1016/j.lfs.2020.118154. Epub 2020 Jul 28.
Epithelial-to-mesenchymal transition (EMT) facilitates cell migration and invasion, and contributes to metastasis in bladder cancer. Within the perioperative period, anesthetic such as isoflurane have been found to affect cancer prognosis. In the study, we reported the tumor-promoting effect of isoflurane in bladder cancer.
Human bladder cancer cell lines T24 and BIU-87 were exposed to isoflurane at different concentrations. The immunofluorescent staining of Ki67, Annexin V-FITC/PI staining, Transwell invasion assays and wound-healing assays were performed to assess cell proliferation, apoptosis, invasion and migration. Expressions of EMT markers (E-cadherin, N-cadherin and Vimentin) and metastatic markers (Snail-1, Slug-1 and MMP-2/9) were determined by immunoblotting. Orthotopic tumor models and mice given tail vein injection of T24 cells were developed with or without 4-h exposure to 2% isoflurane.
We found isoflurane promoted bladder cancer cell proliferation, invasion and migration but reduce apoptosis in a concentration-dependent manner. In addition, isoflurane was shown to increase HIF-1α and its nuclear accumulation in bladder cancer cells. HIF-1α knockdown inhibited bladder cancer cell proliferation and delayed EMT, which was reversed in the presence of 4-h exposure to 2% isoflurane. Likewise, we found isoflurane modulated β-catenin/Notch1 pathways via HIF-1α. In vivo studies showed that isoflurane exposure accelerated formation of orthotopic bladder tumor and promoted hepatic metastases from carcinoma of the bladder.
Taken together, our study demonstrates that a frequently used anesthetic can exert a protumorigenic effect on bladder cancer. Isoflurane may serve as an important contributory factor to high recurrence following surgery.
上皮间质转化（EMT）促进细胞迁移和侵袭，促进膀胱癌转移。在围手术期，发现麻醉剂如异氟醚会影响癌症预后。在这项研究中，我们报告了异氟醚在膀胱癌中的促肿瘤作用。
将人膀胱癌细胞系 T24 和 BIU-87 暴露于不同浓度的异氟醚中。通过免疫荧光染色 Ki67、Annexin V-FITC/PI 染色、Transwell 侵袭实验和划痕愈合实验评估细胞增殖、凋亡、侵袭和迁移。通过免疫印迹测定 EMT 标志物（E-钙黏蛋白、N-钙黏蛋白和波形蛋白）和转移标志物（Snail-1、Slug-1 和 MMP-2/9）的表达。建立了原位肿瘤模型和经尾静脉注射 T24 细胞的小鼠模型，并在或不在 4 小时暴露于 2%异氟醚的情况下进行。
我们发现异氟醚以浓度依赖的方式促进膀胱癌细胞增殖、侵袭和迁移，但减少凋亡。此外，异氟醚增加了膀胱癌细胞中的 HIF-1α 及其核积累。HIF-1α 敲低抑制了膀胱癌细胞的增殖并延迟了 EMT，而在存在 4 小时暴露于 2%异氟醚的情况下则逆转了 EMT。同样，我们发现异氟醚通过 HIF-1α 调节β-连环蛋白/Notch1 通路。体内研究表明，异氟醚暴露加速了原位膀胱癌的形成，并促进了膀胱癌的肝转移。
总之，我们的研究表明，一种常用的麻醉剂对膀胱癌具有促肿瘤作用。异氟醚可能是手术切除后复发率高的一个重要促成因素。
