Mouse double minute 2 (MDM2) upregulates Snail expression and induces epithelial-to-mesenchymal transition in breast cancer cells in vitro and in vivo

Abstract

The oncogene, mouse double minute 2 (MDM2), has been implicated in the pathogenesis of numerous cancers. In this study, we investigated the role of MDM2 in epithelial-to-mesenchymal transition (EMT) and the underlying mechanisms in breast cancer cells in vitro and in vivo. The results showed that up-regulation of MDM2 in MCF-7 cells altered the cell morphology to a mesenchymal phenotype. Knockdown of MDM2 in MDA-MB-231 cells altered the cell morphology to the epithelial phenotype. In addition, overexpression of MDM2 increased the expression of N-cadherin and Vimentin and decreased the expression of E-cadherin, at both the mRNA and protein levels, in vitro and in vivo. Conversely, down-regulation of MDM2 decreased the expression of N-cadherin and Vimentin, and increased the expression of E-cadherin in vitro. Furthermore, MDM2 up-regulated both the mRNA and protein expression of Snail in vitro and in vivo. Knockdown of Snail almost abolished MDM2 induced EMT in vitro. Finally, we found that MDM2 expression correlated with EMT markers and Snail: Snail expression was inversely associated with E-cadherin in human breast cancer samples. Our findings demonstrated that MDM2 induces EMT by enhancing Snail expression in vitro and in vivo. Thus, MDM2 may be a potential target for therapy against human metastatic breast cancer.

Long Non-Coding RNA BC040587 is Required in Cell Invasion of Renal Cancer Induced by Acidosis

“…Moreover, activation of MDM2 elevated the level of Snail, which is critical in cell invasion. Activation of MDM2 was reported to increase Snail level [28]; in consistent with that, inhibition of MDM2 by siRNA signi cantly down-regulated Snail, resulting in decrease of cell invasion. Thus, these data suggests that BC040587/MDM2/Snail is crucial in the cell invasion in response to acidosis.…”

MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells

“…Moreover, in our previous study, we found that a potent and selective small molecular MDM2 antagonist Nutlin3 inhibited TGF- β 1-induced EMT in ovarian cancer cells ( Wu et al , 2014b ), indicating the correlation of MDM2 and EMT in ovarian cancer. A recent study demonstrated that MDM2 induced EMT by enhancing Snail expression ( Lu et al , 2016 ); however, whether MDM2 is involved in the TGF- β -Smad signalling pathway thus promoting the progression of EMT remains unclear.…”

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

“…In addition, the snail family of zinc-finger transcription factors (snail, slug, and smuc) have been identified as key EMT regulators, and are the ‘master switches’ critical for cell reprogramming8. Recent studies have shown that snail is a key transcription factor involved in the development of EMT, which could repress the expression of E-cadherin by direct binding to the E-box on its promoter, thereby promoting the progression of EMT910.…”