食管腺癌的癌干细胞被TRPV2和SLC12A2的抑制剂抑制
Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2
影响因子:3.50000
分区:医学2区 / 外科2区 肿瘤学3区
发表日期:2023 Dec
作者:
Atsushi Shiozaki, Hiroyuki Inoue, Hiroki Shimizu, Toshiyuki Kosuga, Kenichi Takemoto, Michihiro Kudou, Takuma Ohashi, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Takeshi Kubota, Hitoshi Fujiwara, Eigo Otsuji
摘要
作为癌症的新治疗靶标在癌症干细胞（CSC）中激活的膜转运蛋白的潜力正在吸引越来越多的兴趣。因此，本研究检查了食管腺癌CSC中离子转运相关分子的表达谱图（EAC）。高表达醛脱氢酶1家族成员A1（ALDH1A1）的细胞与人类Barrett的EACC Cell Line，通过液体分析，将其分离为flumentiv。根据肿瘤球的形成确定CSC。通过微阵列分析检查了CSC中的基因表达谱。在OE33细胞中，CSC中的ALDH1A1信使RNA水平高于非CSC。此外，CSC表现出对顺铂的抗性，并具有重新分化的能力。 CSC的微阵列分析的结果表明，几种与离子通道/转运蛋白有关的基因的上调表达，例如瞬态受体电势香草素2（TRPV2）和溶质载体家族12构件2（SLC12A2）。 TRPV2抑制剂tranilast和SLC12A2抑制剂速尿的细胞毒性在CSC中低于非CSC的浓度高，并且都显着减少了肿瘤球的数量。这些抑制剂的高度表达ALDH1A1的OE33细胞中的细胞群也显着降低。基于目前的结果，TRPV2和SLC12A2参与了CSC的维持，分别具有特定的抑制剂，Tranilast和tranilast和furosemide的特异性抑制剂，具有靶向靶向的EACENTEAPETEDERAPETECUTIC ANSEAPETIC AGENT。
Abstract
The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC).Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis.Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors.Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.