Tomohiro Kohmoto1,2, Kiyoshi Masuda3, Katsutoshi Shoda4, Rizu Takahashi1, Sae Ujiro1, Shoichiro Tange1, Daisuke Ichikawa5, Eigo Otsuji4, Issei Imoto6,7,8. 1. Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Tokushima, 770-8503, Japan. 2. Division of Molecular Genetics, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. 3. Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan. 4. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, 602-8566, Japan. 5. First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan. 6. Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Tokushima, 770-8503, Japan. iimoto@aichi-cc.jp. 7. Division of Molecular Genetics, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. iimoto@aichi-cc.jp. 8. Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan. iimoto@aichi-cc.jp.
Abstract
BACKGROUND: We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients. METHODS: Genes whose expression was increased and correlated with worse prognosis in GC were screened using datasets from the Cancer Genome Atlas and Gene Expression Omnibus. We examined Claudin-6 (CLDN6) immunoreactivity in GC tissues and the effect of CLDN6 on cellular functions in GC cell lines. The mechanisms underlying GC-promoting function of CLDN6 were also investigated. RESULTS: CLDN6 was identified as a gene overexpressed in GC tumors as compared with adjacent non-tumorous tissues and whose increased expression was positively correlated with worse overall survival of GC patients, particularly those with Lauren's intestinal type GC, in data from multiple publicly available datasets. Additionally, membranous CLDN6 immunoreactivity detected in intestinal type GC tumors was correlated with worse overall survival. In CLDN6-expressing GC cells, silencing of CLDN6 inhibited cell proliferation and migration/invasion abilities, possibly via suppressing transcription of YAP1 and its downstream transcriptional targets at least in part. CONCLUSIONS: This study identified CLDN6 as a GC-promoting gene, suggesting that CLDN6 to be a possible single prognostic marker and promising therapeutic target for a subset of GC patients.
BACKGROUND: We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients. METHODS: Genes whose expression was increased and correlated with worse prognosis in GC were screened using datasets from the Cancer Genome Atlas and Gene Expression Omnibus. We examined Claudin-6 (CLDN6) immunoreactivity in GC tissues and the effect of CLDN6 on cellular functions in GC cell lines. The mechanisms underlying GC-promoting function of CLDN6 were also investigated. RESULTS:CLDN6 was identified as a gene overexpressed in GC tumors as compared with adjacent non-tumorous tissues and whose increased expression was positively correlated with worse overall survival of GCpatients, particularly those with Lauren's intestinal type GC, in data from multiple publicly available datasets. Additionally, membranous CLDN6 immunoreactivity detected in intestinal type GC tumors was correlated with worse overall survival. In CLDN6-expressing GC cells, silencing of CLDN6 inhibited cell proliferation and migration/invasion abilities, possibly via suppressing transcription of YAP1 and its downstream transcriptional targets at least in part. CONCLUSIONS: This study identified CLDN6 as a GC-promoting gene, suggesting that CLDN6 to be a possible single prognostic marker and promising therapeutic target for a subset of GCpatients.
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