Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer
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We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients.
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.
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.
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.
KeywordsClaudin-6 Stomach neoplasms Prognosis Computer simulation Oncogenes
This study was supported in part by JSPS KAKENHI, grant number JP18H02894 as a Grant-in-Aid for Scientific Research (B) (to I.I.), 18K07910 as a Grant-in-Aid for Scientific Research (C) (to K.M), and 18J21308 as a Grant-in-Aid for JSPS Research Fellow (to T.K.). We thank Hideaki Horikawa and Akiko Watanabe (Support Center for Advanced Medical Sciences, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan) for their technical assistances.
All of the listed authors contributed to the current study. II conceived and designed the experiments; TK and KM performed the experiments; TK, KM, KS, ST, and II analyzed the data; KS, DI, and EO performed collection of the tissue specimens; and TK, KM, and II wrote the paper. All authors have read and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
None of the authors have conflicts of interest to declare.
All procedures were performed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national), as well as the Helsinki Declaration of 1964 and later versions, and approved by the ethics committee of Kyoto Prefectural University of Medicine.
Informed consent or an acceptable substitute was obtained from all patients prior to inclusion in the study.
Consent for publication
Consent to publish the present findings was obtained from all of the participants.
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