Estrogen-related receptor alpha induces epithelial-mesenchymal transition through cancer-stromal interactions in endometrial cancer

(E)strogen-related receptor alpha (ERR alpha), which shares structural similarities with estrogen receptors, is associated with tumor progression in endometrial cancer, but little is known about the detailed underlying mechanism. We investigated whether ERR alpha, in cooperation with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), could participate in epithelial-mesenchymal transition (EMT) in endometrial cancer through cancer-stromal interactions. Two endometrial cancer cell lines, Ishikawa and HEC-1A, transfected with ERR alpha/PGC-1 alpha expression plasmids or silenced for ERR alpha expression, were co-cultured with telomerase-transformed human endometrial stroma I cells (T-HESCs). We found that EMT-associated factors including vimentin, Snail, and zinc finger E-box binding homeobox 1 were upregulated in cancer cells overexpressing ERR alpha/PGC-1 alpha and that transforming growth factor-beta (TGF-beta) was induced in T-HESCs in the same conditions. In contrast, ERR alpha knockdown suppressed EMT-associated factors in cancer cells and TGF-beta in T-HESCs. ERR alpha/ PGC-1 alpha overexpression increased the expression of EMT-associated factors after TGF-beta exposure; however, it decreased E-cadherin at protein level. ERR alpha knockdown suppressed EMT-associated factors in the presence of TGF-beta, whereas E-cadherin remained unchanged. Matrigel invasion assays revealed that ERR alpha knockdown attenuated the stimulation of migration and invasion byTGF-beta. These findings suggest that ERR alpha is a potential target for inhibiting TGF-beta-induced EMT through cancer-stromal interactions in endometrial cancer.