Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 23; no. 3; pp. 403 - 417
• Main Authors: Kohmoto, Tomohiro, Masuda, Kiyoshi, Shoda, Katsutoshi, Takahashi, Rizu, Ujiro, Sae, Tange, Shoichiro, Ichikawa, Daisuke, Otsuji, Eigo, Imoto, Issei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.05.2020; Springer Nature B.V
• Subjects: Abdominal Surgery; Aged; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; Case-Control Studies; Cell Cycle; Cell migration; Cell Proliferation; Claudins - genetics; Claudins - metabolism; Female; Follow-Up Studies; Gastric cancer; Gastroenterology; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Humans; Immunoreactivity; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestinal Neoplasms - surgery; Intestine; Male; Medical prognosis; Medicine; Medicine & Public Health; Oncology; Original Article; Prognosis; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach Neoplasms - surgery; Surgical Oncology; Survival Rate; Therapeutic applications; Transcription; Tumor Cells, Cultured; Tumors; Yes-associated protein; Claudin-6; Prognosis; Computer simulation; Stomach neoplasms; Oncogenes
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-019-01014-x

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.