食管腺癌的癌症干细胞受到TRPV2和SLC12A2抑制剂的抑制

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2

ANNALS OF SURGICAL ONCOLOGY

影响因子:3.5

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

DOI: 10.1245/s10434-023-14247-z

摘要

膜转运蛋白在癌症干细胞（CSCs）中的激活潜力作为癌症新治疗靶点引起日益关注。因此，本研究检测了食管腺癌（EAC）CSC中离子转运相关分子的表达谱。通过荧光激活细胞分选，从人类Barrett’s食管腺癌细胞系OE33中分离出高表达醛脱氢酶1家族成员A1（ALDH1A1）的细胞。以肿瘤球形成能力作为CSC的标志。采用微阵列分析检测CSC中的基因表达谱。结果显示，OE33细胞中，ALDH1A1的mRNA水平在CSC中高于非CSC。此外，CSC表现出对顺铂的抗药性并具有再分化的能力。微阵列分析结果显示，CSC中多种与离子通道/转运蛋白相关的基因表达上调，如瞬时受体电位香草醇受体2（TRPV2）和溶质载体家族12成员2（SLC12A2）。TRPV2抑制剂tranilast和SLC12A2抑制剂呋塞米在CSC中的细胞毒性在较低浓度下高于非CSC，并显著减少肿瘤球的数量。高度表达ALDH1A1的OE33细胞群体也被这些抑制剂显著减少。基于本研究结果，TRPV2和SLC12A2参与维持CSC的功能，其特异性抑制剂tranilast和呋塞米分别具有作为EAC靶向治疗药物的潜力。

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.