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Updated: Jun 29, 2025
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
Combinatorial Cooperativity in miR200-Zeb Feedback Network can Control Epithelial-Mesenchymal Transition
Mubasher Rashid1, Brasanna M Devi2, Malay Banerjee2
1Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, 208016, India. mubasherrashid@gmail.com.
Abstract:
Carcinomas often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies report SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by placing cancer cells in at least three phenotypic states, viz. epithelial (E), hybrid (h-E/M), mesenchymal (M), along the E-M phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that the miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, h-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences-the circuit can dynamically switch between two (E, M) and three (E, h-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translation inhibition due to miR200 are essential for the occurrence of intermediate h-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to h-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.
Insights
The miR200/Zeb circuit controls cancer cell plasticity using combinatorial cooperativity. This molecular understanding reveals how cancer cells transition between epithelial, hybrid, and mesenchymal states, crucial for preventing metastasis.
Area of Science:
- Molecular biology
- Cancer research
- Systems biology
Background:
- Epithelial-mesenchymal transition (EMT) drives carcinoma progression and metastasis.
- The miR200/Zeb feedback circuit is key in regulating EMT, defining epithelial (E), hybrid (h-E/M), and mesenchymal (M) cell states.
- A detailed molecular understanding of this circuit's control over cell state transitions is lacking.
Purpose of the Study:
- To elucidate the molecular mechanisms by which the miR200/Zeb circuit governs phenotypic plasticity in carcinomas.
- To identify the minimal combinatorial cooperativities responsible for E, h-E/M, and M phenotypes.
- To investigate the role of SNAIL in EMT regulation within the miR200/Zeb circuit.
Main Methods:
- Utilized molecular binding data.
- Employed mathematical modeling to analyze the miR200/Zeb circuit dynamics.
- Investigated phenotypic consequences of altering miR200 and Zeb binding sites.
- Examined circuit behavior in both SNAIL-induced and SNAIL-knockout scenarios.
Main Results:
- The miR200/Zeb circuit employs combinatorial cooperativity to control epithelial-mesenchymal transition (EMT) plasticity.
- Specific disruptions in miR200/Zeb binding sites can alter the number of accessible cell phenotypes (two vs. three).
- Cooperative transcriptional feedback on Zeb and miR200-mediated Zeb translation inhibition are essential for the hybrid epithelial/mesenchymal (h-E/M) state.
- SNAIL can be dispensable for EMT, with transcriptional feedback alone mediating cell state transitions.
Conclusions:
- Combinatorial cooperativity is a fundamental mechanism for miR200/Zeb circuit-mediated EMT regulation.
- The findings provide a molecular-level understanding of cell state transitions in carcinomas.
- These insights are critical for developing strategies to inhibit EMT-facilitated cancer dissemination.
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