Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF-β signaling in uterine leiomyosarcoma cells
Overexpression of carbonyl reductase 1 inhibits malignant behaviors and epithelial mesenchymal transition by suppressing TGF-β signaling in uterine leiomyosarcoma cells
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DOI：
10.3892/ol.2019.10429
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发表时间：
2019-08-01
期刊：
影响因子：
2.9
通讯作者：
Sugino, Norihiro
中科院分区：
文献类型：
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作者：
Kajimura, Takuya;Sato, Shun;Sugino, Norihiro
据报道，羰基还原酶1(CBR1)与肿瘤的进展有关。最近，我们发现CBR1的过表达抑制了宫颈癌的恶性行为和上皮间质转化(EMT)。目前尚不清楚子宫平滑肌肉瘤(ULMS)是否也是如此，它源于间充质细胞，是一种恶性程度更高的妇科肿瘤。以前的一些研究表明，恶性行为与EMT有关，甚至在间叶性恶性肿瘤中也是如此。在本研究中，我们研究了CBR1是否能抑制ULMS的恶性行为和EMT。我们建立了过表达CBR1的ULMS细胞(SKN细胞)和子宫肉瘤细胞(MES-SA细胞)的克隆。CBR1过表达抑制了细胞的增殖、迁移和侵袭活性，伴随着上皮标志物(E-钙粘素和细胞角蛋白)的表达增加，间质标志物(N-钙粘附素和纤维粘连蛋白)的表达减少，提示CBR1过表达抑制了ULMS细胞的恶性行为和EMT。此外，转化生长因子-β(转化生长因子-β)的产生以及随后Smad的信号和磷酸化在克隆中受到抑制。为了研究转化生长因子-β与子宫内膜间质转化的关系，用转化生长因子-β或转化生长因子-β受体阻滞剂(SB431542)处理SKN细胞。转化生长因子-β促进EMT，SB431542抑制EMT。总之，据作者所知，这是第一项表明CBR1过表达抑制UMS细胞恶性行为和EMT的研究。本研究提供了新的见解，证明CBR1的抑制作用是通过转化生长因子-β信号介导的。
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 fibronectin), suggesting that CBR1 overexpression inhibits malignant behaviors and EMT in uLMS cells. In addition, transforming growth factor-beta (TGF-beta) production and the subsequent signaling and phosphorylation of Smad were suppressed in the clones. To investigate the association between TGF-beta and EMT, SKN cells were treated with TGF-beta or a TGF-beta receptor blocker (SB431542). EMT was promoted by TGF-beta 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-beta signaling.