Research Papers:

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

Ryuta Inoue, Yoshihiko Hirohashi, Hiroshi Kitamura, Sachiyo Nishida, Aiko Murai, Akari Takaya, Eri Yamamoto, Masahiro Matsuki, Toshiaki Tanaka, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Noriyuki Sato, Naoya Masumori and Toshihiko Torigoe _

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Oncotarget. 2017; 8:28826-28839. https://doi.org/10.18632/oncotarget.16259

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Ryuta Inoue1,2, Yoshihiko Hirohashi1, Hiroshi Kitamura3, Sachiyo Nishida1,2, Aiko Murai1, Akari Takaya1, Eri Yamamoto1, Masahiro Matsuki1,2, Toshiaki Tanaka2, Terufumi Kubo1, Munehide Nakatsugawa1, Takayuki Kanaseki1, Tomohide Tsukahara1, Noriyuki Sato1, Naoya Masumori2, Toshihiko Torigoe1

1Department of Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan

2Department of Urology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan

3Department of Urology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama-Shi 930-0194, Japan

Correspondence to:

Yoshihiko Hirohashi, email: hirohash@sapmed.ac.jp

Toshihiko Torigoe, email: torigoe@sapmed.ac.jp

Keywords: cancer stem-like cells, ALDH1, GRIK2, urothelial carcinoma

Received: June 29, 2016     Accepted: February 20, 2017     Published: March 16, 2017


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.

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