Aberrant claudin-6–adhesion signal promotes endometrial cancer progression via estrogen receptor a

Cell adhesion proteins not only maintain tissue integrity but also possess signaling abilities to organize diverse cellular events in a variety of physiological and pathological processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family often possesses aberrant expression in various cancers, but the biological relevance and molecular basis have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in human endometrial cancer cells in vitro. Using xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFKs) and to stimulate malignant phenotypes. Importantly, we demonstrate that the CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signalings target Ser518 in the human estrogen receptor a and ligand-independently activate target genes in endometrial cancer cells, resulting in cancer development. CLDN6, at least in part, also regulated gene expression in an ERa-independent manner. Overall design: RNA-seq analysis was performed using wild-type (WT) and CLDN6-overexpressed Ishikawa cell lines.