Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF-β signaling in uterine leiomyosarcoma cells

Abstract

Carbonyl reductase 1 (CBR1) has been reported to be involved in cancer progression. Recently, we found that CBR1 overexpression inhibited malignant behaviors and the epithelial mesenchymal transition (EMT) in uterine cervical cancer. It remained unclear whether this was also the case in uterine leiomyosarcoma (uLMS), which is derived from mesenchymal cells and is a much more malignant gynecological tumor. A number of previous studies suggested that malignant behaviors are associated with EMT, even in mesenchymal malignant tumors. In the present study, we investigated whether CBR1 inhibits malignant behaviors and EMT in uLMS. We established clones of uLMS cells (SKN cells) and uterine sarcoma cells (MES-SA cells) that overexpressed CBR1. Cell proliferative, migratory and invasive activities were suppressed by CBR1 overexpression, accompanied by increases in the expressions of epithelial markers (E-cadherin and cytokeratin) and decreases in the expressions of mesenchymal markers (N-cadherin and fibro-nectin), suggesting that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells. In addition, transforming growth factor-β (TGF-β) production and the subsequent signaling and phosphorylation of Smad were suppressed in the clones. To investigate the association between TGF-β and EMT, SKN cells were treated with TGF-β or a TGF-β receptor blocker (SB431542). EMT was promoted by TGF-β and inhibited by SB431542. In conclusion, this is the first study, to the best of the authors' knowledge, showing that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells. The present study provided novel insight demonstrating that the suppressive effect of CBR1 is mediated through TGF-β signaling.