GRIK2 has a role in the maintenance of urothelial carcinoma stem-like cells, and its expression is associated with poorer prognosis

• Published in: Oncotarget 2017-04, Vol.8 (17), p.28826-28839
• Main Authors: Inoue, Ryuta, Hirohashi, Yoshihiko, Kitamura, Hiroshi, Nishida, Sachiyo, Murai, Aiko, Takaya, Akari, Yamamoto, Eri, Matsuki, Masahiro, Tanaka, Toshiaki, Kubo, Terufumi, Nakatsugawa, Munehide, Kanaseki, Takayuki, Tsukahara, Tomohide, Sato, Noriyuki, Masumori, Naoya, Torigoe, Toshihiko
• Format: Article
• Language: English
• Subjects: Aldehyde Dehydrogenase 1 Family; Animals; Carcinogenesis; Cell Line, Tumor; Cell Self Renewal - genetics; Female; Gene Expression Regulation, Neoplastic; GluK2 Kainate Receptor; Humans; Isoenzymes - metabolism; Mice; Mice, SCID; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Receptors, Kainic Acid - genetics; Receptors, Kainic Acid - metabolism; Research Paper; Retinal Dehydrogenase - metabolism; RNA, Small Interfering - genetics; Urologic Neoplasms - diagnosis; Urologic Neoplasms - genetics; Urologic Neoplasms - pathology; Urothelium - pathology; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.16259

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are small sub-population of cancer cells that are endowed with higher tumor-initiating ability, self-renewal ability and differentiation ability. CSCs/CICs could be isolated as high aldehyde dehydrogenase 1 activity cells (ALDH1high) from various cancer samples. In this study, we isolated urothelial carcinoma CSCs/CICs as ALDHhigh cells and investigated the molecular aspects. ALDH1high cells showed greater sphere-forming ability and higher tumor-initiating ability in immune-deficient mice than those of ALDH1low cells, indicating that CSCs/CICs were enriched in ALDH1high cells. cDNA microarray analysis revealed that an ionotropic glutamate receptor glutamate receptor, ionotropic, kainate 2 (GRIK2) was expressed in ALDH1high cells at a higher level than that in ALDH1low cells. GRIK2 gene knockdown by siRNAs decreased the sphere-forming ability and invasion ability, whereas GRIK2 overexpression increased the sphere-forming ability, invasion ability and tumorigenicity, indicating that GRIK2 has a role in the maintenance of CSCs/CICs. Immunohistochemical staining revealed that higher levels of GRIK2 and ALDH1 expression were related to poorer prognosis in urinary tract carcinoma cases. The findings indicate that GRIK2 has a role in the maintenance of urothelial CSCs/CICs and that GRIK2 and ALDH1 can be prognosis prediction markers for urinary tract carcinomas.