A Novel Network Integrating a miRNA-203/SNAI1 Feedback Loop which Regulates Epithelial to Mesenchymal Transition

Abstract

BackgroundThe majority of human cancer deaths are caused by metastasis. The metastatic dissemination is initiated by the breakdown of epithelial cell homeostasis. During this phenomenon, referred to as epithelial to mesenchymal transition (EMT), cells change their genetic and trancriptomic program leading to phenotypic and functional alterations. The challenge of understanding this dynamic process resides in unraveling regulatory networks involving master transcription factors (e.g. SNAI1/2, ZEB1/2 and TWIST1) and microRNAs. Here we investigated microRNAs regulated by SNAI1 and their potential role in the regulatory networks underlying epithelial plasticity.ResultsBy a large-scale analysis on epithelial plasticity, we highlighted miR-203 and its molecular link with SNAI1 and the miR-200 family, key regulators of epithelial homeostasis. During SNAI1-induced EMT in MCF7 breast cancer cells, miR-203 and miR-200 family members were repressed in a timely correlated manner. Importantly, miR-203 repressed endogenous SNAI1, forming a double negative miR203/SNAI1 feedback loop. We integrated this novel miR203/SNAI1 with the known miR200/ZEB feedback loops to construct an a priori EMT core network. Dynamic simulations revealed stable epithelial and mesenchymal states, and underscored the crucial role of the miR203/SNAI1 feedback loop in state transitions underlying epithelial plasticity.ConclusionBy combining computational biology and experimental approaches, we propose a novel EMT core network integrating two fundamental negative feedback loops, miR203/SNAI1 and miR200/ZEB. Altogether our analysis implies that this novel EMT core network could function as a switch controlling epithelial cell plasticity during differentiation and cancer progression.

Circulating microRNA-203 predicts metastases, early recurrence, and poor prognosis in human gastric cancer

“…In cancer metastasis, EMT is a key process that converts polarized immotile epithelial cells into motile invasive mesenchymal cells, which subsequently enables cancer cells to acquire stem cell characteristics and aggressive malignant properties [34,35]. MiR-203 has been shown to directly suppress EMT activators such as ZEB2 and SNAI1/2 in various types of cancer [32,[36][37][38].…”

Biomarkers for EMT and MET in breast cancer: An update

“…In particular, miR-203 represses endogenous Snail, forming a double-negative miR-203/Snail feedback loop (89). In addition, miR-203 is also able to target Slug.…”

microRNA: New Players in Metastatic Process

“…Recently, miR-203 was reported as a metastasis suppressor miRNA, targeting Slug [34] and Snail1 [35] and is often silenced in different malignancies including hepatocellular carcinoma, prostate cancer, oral cancer, breast cancer and hematopoietic malignancy. Snail1 and Slug play a key role during the early step of EMT, activating expression of ZEB factors in a context-dependent manner.…”