Abstract
Estrogen-related receptor alpha (ERRα), 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 ERRα, in cooperation with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), 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 ERRα/PGC-1α expression plasmids or silenced for ERRα expression, were co-cultured with telomerase-transformed human endometrial stromal 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 ERRα/PGC-1α and that transforming growth factor-beta (TGF-β) was induced in T-HESCs in the same conditions. In contrast, ERRα knockdown suppressed EMT-associated factors in cancer cells and TGF-β in T-HESCs. ERRα/PGC-1α overexpression increased the expression of EMT-associated factors after TGF-β exposure; however, it decreased E-cadherin at protein level. ERRα knockdown suppressed EMT-associated factors in the presence of TGF-β, whereas E-cadherin remained unchanged. Matrigel invasion assays revealed that ERRα knockdown attenuated the stimulation of migration and invasion by TGF-β. These findings suggest that ERRα is a potential target for inhibiting TGF-β-induced EMT through cancer-stromal interactions in endometrial cancer.
Highlights
Endometrial cancer is a leading cause of female genital tract malignancies, and its incidence and death rates have been notably increasing
To investigate the cancer-stromal interactions through ERRα in endometrial cancer, human endometrial fibroblasts immortalized with human telomerase reverse transcriptase (T-HESCs) were co-cultured with Ishikawa or www.nature.com/scientificreports
The expression of vimentin, Snail, and zinc finger E-box binding homeobox 1 (ZEB1) in Ishikawa (E) and HEC-1A (F) cells co-cultured with transformed human endometrial stromal cells (T-HESCs), after ERRα knockdown, was examined by Quantitative polymerase chain reaction (qPCR)
Summary
Endometrial cancer is a leading cause of female genital tract malignancies, and its incidence and death rates have been notably increasing. The tumor microenvironment includes the extracellular matrix (collagen and hyaluronic acid) and many secreted soluble factors, such as Wnt, transforming growth factor beta (TGF-β), Hedgehog, epidermal growth factor, hepatocyte growth factor, and cytokines[9,10] Among these signals, TGF-β is the most potent inducer of EMT. TGF-β typically has tumor-suppressing activity in normal cells and early-stage cancers through its ability to induce cell cycle arrest and apoptosis. It can serve as a positive regulator of tumor progression and metastasis[5,11,12]. We investigated whether ERRα could activate EMT of cancer cells through cancer-stromal interactions and thereby promote invasion and metastasis in endometrial cancer
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