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Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives.

Díaz-López A, Moreno-Bueno G, Cano A - Cancer Manag Res (2014)

Bottom Line: The EMT triggering leads to the activation of a core of transcription factors (EMT-TFs) - SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2 - that act as E-cadherin repressors and, ultimately, coordinate EMT.Recent evidence indicates that several miRNAs regulate the expression of EMT-TFs or EMT-activating signaling pathways.Among the most significant feedback loops, we focus on the ZEB/miR-200 and the SNAIL1/miR-34 networks that hold a clear impact in the regulation of the epithelial-mesenchymal state.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.

ABSTRACT
The microRNAs (miRNAs) are a class of small, 20-22 nucleotides in length, endogenously expressed noncoding RNAs that regulate multiple targets posttranscriptionally. Interestingly, miRNAs have emerged as regulators of most physiological and pathological processes, including metastatic tumor progression, in part by controlling a reversible process called epithelial-to-mesenchymal transition (EMT). The activation of EMT increases the migratory and invasive properties fundamental for tumor cell spread while activation of the reverse mesenchymal-to-epithelial transition is required for metastasis outgrowth. The EMT triggering leads to the activation of a core of transcription factors (EMT-TFs) - SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2 - that act as E-cadherin repressors and, ultimately, coordinate EMT. Recent evidence indicates that several miRNAs regulate the expression of EMT-TFs or EMT-activating signaling pathways. Interestingly, some miRNAs and EMT-TFs form tightly interconnected negative feedback loops that control epithelial cell plasticity, providing self-reinforcing signals and robustness to maintain the epithelial or mesenchymal cell status. Among the most significant feedback loops, we focus on the ZEB/miR-200 and the SNAIL1/miR-34 networks that hold a clear impact in the regulation of the epithelial-mesenchymal state. Recent insights into the p53 modulation of the EMT-TF/miRNA loops and epigenetic regulatory mechanisms in the context of metastasis dissemination will also be discussed. Understanding the regulation of EMT by miRNAs opens new avenues for the diagnosis and prognosis of tumors and identifies potential therapeutic targets that might help to negatively impact on metastasis dissemination and increasing patient survival.

No MeSH data available.


Related in: MedlinePlus

miRNA and EMT-TF regulatory networks controlling epithelial plasticity.Notes: EMT-TFs positively regulate the expression of other EMT-TFs in a tightly hierarchical regulated network. Different miRNAs negatively regulate core EMT-TFs, and some of them orchestrate negative feedback loops reinforcing the system. Epigenetic regulation of some miRNAs provides additional robustness to the EMT program.Abbreviations: miRNA, microRNA; TET, ten-eleven translocation; EMT, epithelial-to-mesenchymal transition; TF, transcription factor.
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f1-cmar-6-205: miRNA and EMT-TF regulatory networks controlling epithelial plasticity.Notes: EMT-TFs positively regulate the expression of other EMT-TFs in a tightly hierarchical regulated network. Different miRNAs negatively regulate core EMT-TFs, and some of them orchestrate negative feedback loops reinforcing the system. Epigenetic regulation of some miRNAs provides additional robustness to the EMT program.Abbreviations: miRNA, microRNA; TET, ten-eleven translocation; EMT, epithelial-to-mesenchymal transition; TF, transcription factor.

Mentions: Another mechanism to control epithelial plasticity is regulating those pathways controlling EMT. Recently, several miRNAs that directly impinge on the regulation of EMT-TFs have been described; some of them operate in double negative feedback loops that contribute to maintain the epithelial or mesenchymal states29–31 (Figure 1). In addition, these EMT-regulatory miRNA networks can be controlled by EMT-inducing signals, like TGF-β signaling, and/or by p53, implementing additional levels of regulation and providing robustness to the system. In this review, we will discuss the most relevant miRNA-EMT-TF networks discovered to date.


Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives.

Díaz-López A, Moreno-Bueno G, Cano A - Cancer Manag Res (2014)

miRNA and EMT-TF regulatory networks controlling epithelial plasticity.Notes: EMT-TFs positively regulate the expression of other EMT-TFs in a tightly hierarchical regulated network. Different miRNAs negatively regulate core EMT-TFs, and some of them orchestrate negative feedback loops reinforcing the system. Epigenetic regulation of some miRNAs provides additional robustness to the EMT program.Abbreviations: miRNA, microRNA; TET, ten-eleven translocation; EMT, epithelial-to-mesenchymal transition; TF, transcription factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4008290&req=5

f1-cmar-6-205: miRNA and EMT-TF regulatory networks controlling epithelial plasticity.Notes: EMT-TFs positively regulate the expression of other EMT-TFs in a tightly hierarchical regulated network. Different miRNAs negatively regulate core EMT-TFs, and some of them orchestrate negative feedback loops reinforcing the system. Epigenetic regulation of some miRNAs provides additional robustness to the EMT program.Abbreviations: miRNA, microRNA; TET, ten-eleven translocation; EMT, epithelial-to-mesenchymal transition; TF, transcription factor.
Mentions: Another mechanism to control epithelial plasticity is regulating those pathways controlling EMT. Recently, several miRNAs that directly impinge on the regulation of EMT-TFs have been described; some of them operate in double negative feedback loops that contribute to maintain the epithelial or mesenchymal states29–31 (Figure 1). In addition, these EMT-regulatory miRNA networks can be controlled by EMT-inducing signals, like TGF-β signaling, and/or by p53, implementing additional levels of regulation and providing robustness to the system. In this review, we will discuss the most relevant miRNA-EMT-TF networks discovered to date.

Bottom Line: The EMT triggering leads to the activation of a core of transcription factors (EMT-TFs) - SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2 - that act as E-cadherin repressors and, ultimately, coordinate EMT.Recent evidence indicates that several miRNAs regulate the expression of EMT-TFs or EMT-activating signaling pathways.Among the most significant feedback loops, we focus on the ZEB/miR-200 and the SNAIL1/miR-34 networks that hold a clear impact in the regulation of the epithelial-mesenchymal state.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.

ABSTRACT
The microRNAs (miRNAs) are a class of small, 20-22 nucleotides in length, endogenously expressed noncoding RNAs that regulate multiple targets posttranscriptionally. Interestingly, miRNAs have emerged as regulators of most physiological and pathological processes, including metastatic tumor progression, in part by controlling a reversible process called epithelial-to-mesenchymal transition (EMT). The activation of EMT increases the migratory and invasive properties fundamental for tumor cell spread while activation of the reverse mesenchymal-to-epithelial transition is required for metastasis outgrowth. The EMT triggering leads to the activation of a core of transcription factors (EMT-TFs) - SNAIL1/SNAIL2, bHLH (E47, E2-2, and TWIST1/TWIST2), and ZEB1/ZEB2 - that act as E-cadherin repressors and, ultimately, coordinate EMT. Recent evidence indicates that several miRNAs regulate the expression of EMT-TFs or EMT-activating signaling pathways. Interestingly, some miRNAs and EMT-TFs form tightly interconnected negative feedback loops that control epithelial cell plasticity, providing self-reinforcing signals and robustness to maintain the epithelial or mesenchymal cell status. Among the most significant feedback loops, we focus on the ZEB/miR-200 and the SNAIL1/miR-34 networks that hold a clear impact in the regulation of the epithelial-mesenchymal state. Recent insights into the p53 modulation of the EMT-TF/miRNA loops and epigenetic regulatory mechanisms in the context of metastasis dissemination will also be discussed. Understanding the regulation of EMT by miRNAs opens new avenues for the diagnosis and prognosis of tumors and identifies potential therapeutic targets that might help to negatively impact on metastasis dissemination and increasing patient survival.

No MeSH data available.


Related in: MedlinePlus