Atsushi Shiozaki1, Yosuke Ariyoshi2, Daisuke Iitaka2, Toshiyuki Kosuga2, Hiroki Shimizu2,3, Michihiro Kudou2, Tomoki Konishi2, Katsutoshi Shoda2, Tomohiro Arita2, Hirotaka Konishi2, Shuhei Komatsu2, Takeshi Kubota2, Hitoshi Fujiwara2, Kazuma Okamoto2, Mitsuo Kishimoto4, Eiichi Konishi4, Yoshinori Marunaka5,6, Daisuke Ichikawa2,3, Eigo Otsuji2. 1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan. shiozaki@koto.kpu-m.ac.jp. 2. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan. 3. Department of Gastrointestinal, Breast and Endocrine Surgery, Faculty of Medicine, University of Yamanashi, Chuo, 409-3898, Japan. 4. Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan. 5. Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan. 6. Japan Institute for Food Education and Health, St. Agnes' University, Kyoto, 602-8013, Japan.
Abstract
BACKGROUND: Recent studies have described important roles for the sodium iodide symporter (NIS) in tumor behavior. The objectives of the present study were to investigate the role of NIS in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in gastric cancer (GC). METHODS: In human GC cell lines, knockdown experiments were conducted using NIS siRNA, and the effects on proliferation, survival, and cellular movement were analyzed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical analysis was performed on 145 primary tumor samples obtained from GC patients. RESULTS: NIS was strongly expressed in MKN45 and MKN74 cells. The depletion of NIS inhibited cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that various interferon (IFN) signaling-related genes, such as STAT1, STAT2, IRF1, and IFIT1, were up-regulated in NIS-depleted MKN45 cells. Furthermore, the down-regulation of NIS affected the phosphorylation of MAPKs and NF-kB. Immunohistochemical staining showed that NIS was primarily located in the cytoplasm or cell membranes of carcinoma cells, and its expression was related to the histological type or venous invasion. Prognostic analyses revealed that the strong expression of NIS was associated with shorter postoperative survival. CONCLUSIONS: These results suggest that NIS regulates tumor progression by affecting IFN signaling, and that its strong expression is related to a worse prognosis in patients with GC. These results provide an insight into the role of NIS as a mediator and/or a biomarker for GC.
BACKGROUND: Recent studies have described important roles for the sodium iodide symporter (NIS) in tumor behavior. The objectives of the present study were to investigate the role of NIS in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in gastric cancer (GC). METHODS: In human GC cell lines, knockdown experiments were conducted using NIS siRNA, and the effects on proliferation, survival, and cellular movement were analyzed. The gene expression profiles of cells were examined using a microarray analysis. An immunohistochemical analysis was performed on 145 primary tumor samples obtained from GC patients. RESULTS:NIS was strongly expressed in MKN45 and MKN74 cells. The depletion of NIS inhibited cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that various interferon (IFN) signaling-related genes, such as STAT1, STAT2, IRF1, and IFIT1, were up-regulated in NIS-depleted MKN45 cells. Furthermore, the down-regulation of NIS affected the phosphorylation of MAPKs and NF-kB. Immunohistochemical staining showed that NIS was primarily located in the cytoplasm or cell membranes of carcinoma cells, and its expression was related to the histological type or venous invasion. Prognostic analyses revealed that the strong expression of NIS was associated with shorter postoperative survival. CONCLUSIONS: These results suggest that NIS regulates tumor progression by affecting IFN signaling, and that its strong expression is related to a worse prognosis in patients with GC. These results provide an insight into the role of NIS as a mediator and/or a biomarker for GC.
Authors: Julia Schnoell; Ulana Kotowski; Bernhard J Jank; Stefan Stoiber; Elisabeth Gurnhofer; Michaela Schlederer; Gregor Heiduschka; Lukas Kenner; Lorenz Kadletz-Wanke Journal: J Pers Med Date: 2021-12-12