Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric
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ORIGINAL ARTICLE
Claudin‑6 is a single prognostic marker and functions as a tumor‑promoting gene in a subgroup of intestinal type gastric cancer Tomohiro Kohmoto1,2 · Kiyoshi Masuda3 · Katsutoshi Shoda4 · Rizu Takahashi1 · Sae Ujiro1 · Shoichiro Tange1 · Daisuke Ichikawa5 · Eigo Otsuji4 · Issei Imoto1,2,6 Received: 17 July 2019 / Accepted: 12 October 2019 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019
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. Keywords Claudin-6 · Stomach neoplasms · Prognosis · Computer simulation · Oncogenes
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-019-01014-x) contains supplementary material, which is available to authorized users. * Issei Imoto iimoto@aichi‑cc.jp 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
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and third leading cause of cancer death worldwide [1]. Despite important advances for clarification of the etiology and molecular basis, as well as development of treatment strategies, survival rates for affected patients remain poor [2]. 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 40
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