Chloride intracellular channel 1 as a switch among tumor behaviors in human esophageal squamous cell carcinoma

// Toshiyuki Kobayashi 1, * , Atsushi Shiozaki 1, * , Yoshito Nako 1 , Daisuke Ichikawa 1, 2 , Toshiyuki Kosuga 1 , Katsutoshi Shoda 1 , Tomohiro Arita 1 , Hirotaka Konishi 1 , Shuhei Komatsu 1 , Takeshi Kubota 1 , Hitoshi Fujiwara 1 , Kazuma Okamoto 1 , Mitsuo Kishimoto 3 , Eiichi Konishi 3 , Yoshinori Marunaka 4, 5 and Eigo Otsuji 1 1 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan 2 Department of Gastrointestinal, Breast & Endocrine Surgery, Faculty of Medicine, University of Yamanashi, Chuo, 409-3898, Japan 3 Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan 4 Departments of Molecular Cell Physiology and Bio-Ionomics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan 5 Japan Institute for Food Education and Health, St. Agnes’ University, Kyoto, 602-8013, Japan * These authors have contributed equally to this work Correspondence to: Atsushi Shiozaki, email: shiozaki@koto.kpu-m.ac.jp Keywords: CLIC1; esophageal squamous cell carcinoma; TLR2/JNK pathway; tumor survival; cellular movement Received: January 22, 2018     Accepted: April 10, 2018     Published: May 01, 2018 ABSTRACT Background: Recent studies have reported important roles for chloride intracellular channel 1 (CLIC1) in various cancers; however, its involvement in esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of the present study was to investigate the role of CLIC1 in human ESCC. Methods: CLIC1 expression in human ESCC cell lines was analyzed by Western blotting. Knockdown experiments were conducted with CLIC1 siRNA, and their effects on cell proliferation, the cell cycle, apoptosis, migration, and invasion were analyzed. The gene expression profiles of cells were analyzed using a microarray analysis. An immunohistochemical analysis was performed on 61 primary tumor samples obtained from ESCC patients who underwent esophagectomy. Results: ESCC cells strongly expressed CLIC1. The depletion of CLIC1 using siRNA inhibited cell proliferation, induced apoptosis, and promoted cell migration and invasion. The results of the microarray analysis revealed that the depletion of CLIC1 regulated apoptosis via the TLR2/JNK pathway. Immunohistochemistry showed that CLIC1 was present in the cytoplasm of carcinoma cells, and that the very strong or very weak expression of CLIC1 was an independent poor prognostic factor. Conclusions: The present results suggest that the very strong expression of CLIC1 enhances tumor survival, while its very weak expression promotes cellular movement. The present study provides an insight into the role of CLIC1 as a switch among tumor behaviors in ESCC.