Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells

作者：Zhou, Jiesi; Jain, Saket; Azad, Abul K.; Xu, Xia; Yu, Hai Chuan; Xu, Zhihua; Godbout, Roseline; Fu, YangXin^*

来源：Cellular Signalling, 2016, 28(8): 838-849.

DOI：10.1016/j.cellsig.2016.03.016

• Epithelial ovarian cancer
• Notch
• TGF beta
• EMT

Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notchl induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notchl increases TGF(beta/Smad signaling by upregulating the expression of TGF beta and TGF beta type 1 receptor. Time course experiments demonstrate that inhibition of Notch by DAPT (a gamma-secretase inhibitor) decreases TGF beta-induced phosphorylation of receptor Smads at late, but not at early, timepoints. These results suggest that Notch activation plays a role in sustaining TGF beta/Smad signaling in EOC cells. Furthermore, inhibition of Notch by DAPT decreases TGFf3 induction of Slug and repression of E-cadherin and knockdown of Notchl decreases TGF beta-induced repression of Ecadherin, indicating that Notch is required, at least in part, for TGF beta-induced EMT in EOC cells. On the other hand, TGFf3 treatment increases the expression of Notch ligand Jagged1 and Notch target gene HES1 in EOC cells. Functionally, the combination of Notchl activation and TGFf3 treatment is more potent in promoting motility and migration of EOC cells than either stimulation alone. Taken together, our results indicate that Notch and TGF beta form a reciprocal positive regulatory loop and cooperatively regulate EMT and promote EOC cell motility and migration.

• 出版日期2016-8
• 单位汕头大学