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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

The p53 modulation of miRNA-EMT-TF networks.Notes: The p53 positively regulates several miRNAs that downregulate different EMT-TFs or act by indirect mechanism on EMT regulation (ie, miR-145). Most of the p53-regulated miRNAs are involved in double-negative regulatory loops.Abbreviations: miRNA, microRNA; EMT, epithelial-to-mesenchymal transition; TF, transcription factors.
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f2-cmar-6-205: The p53 modulation of miRNA-EMT-TF networks.Notes: The p53 positively regulates several miRNAs that downregulate different EMT-TFs or act by indirect mechanism on EMT regulation (ie, miR-145). Most of the p53-regulated miRNAs are involved in double-negative regulatory loops.Abbreviations: miRNA, microRNA; EMT, epithelial-to-mesenchymal transition; TF, transcription factors.

Mentions: Additionally, p53 indirectly controls EMT by the transcriptional regulation of other miRNAs. AP4, a transcription factor recently described as a new EMT inducer,91 is indirectly regulated by p53 through the expression of miR-15a/16-1 in colorectal cancer cells.92 Ectopic expression of miR-15/miR-16-1 suppresses lung metastatic colonization in a xenograft model. Conversely, AP4 inhibits miR-15/miR-16-1 expression defining a novel negative regulatory loop92 (Figure 2). Wild type p53 also controls EMT and stemness properties in the prostate cancer cell line PC-3, at least in part, by enhancing the expression of miR-145. Accordingly, anti-miR-145 partially reverts this phenotype.93 Collectively, all these findings define a new link between chromosome stability, p53, miRNA expression, cell differentiation, and epithelial plasticity that can be potentially used by cancer cells for the initial stages of metastatic tumor progression, such as invasion or intravasation.


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)

The p53 modulation of miRNA-EMT-TF networks.Notes: The p53 positively regulates several miRNAs that downregulate different EMT-TFs or act by indirect mechanism on EMT regulation (ie, miR-145). Most of the p53-regulated miRNAs are involved in double-negative regulatory loops.Abbreviations: miRNA, microRNA; EMT, epithelial-to-mesenchymal transition; TF, transcription factors.
© Copyright Policy
Related In: Results  -  Collection

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

f2-cmar-6-205: The p53 modulation of miRNA-EMT-TF networks.Notes: The p53 positively regulates several miRNAs that downregulate different EMT-TFs or act by indirect mechanism on EMT regulation (ie, miR-145). Most of the p53-regulated miRNAs are involved in double-negative regulatory loops.Abbreviations: miRNA, microRNA; EMT, epithelial-to-mesenchymal transition; TF, transcription factors.
Mentions: Additionally, p53 indirectly controls EMT by the transcriptional regulation of other miRNAs. AP4, a transcription factor recently described as a new EMT inducer,91 is indirectly regulated by p53 through the expression of miR-15a/16-1 in colorectal cancer cells.92 Ectopic expression of miR-15/miR-16-1 suppresses lung metastatic colonization in a xenograft model. Conversely, AP4 inhibits miR-15/miR-16-1 expression defining a novel negative regulatory loop92 (Figure 2). Wild type p53 also controls EMT and stemness properties in the prostate cancer cell line PC-3, at least in part, by enhancing the expression of miR-145. Accordingly, anti-miR-145 partially reverts this phenotype.93 Collectively, all these findings define a new link between chromosome stability, p53, miRNA expression, cell differentiation, and epithelial plasticity that can be potentially used by cancer cells for the initial stages of metastatic tumor progression, such as invasion or intravasation.

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