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Epithelial Plasticity in Cancer: Unmasking a MicroRNA Network for TGF-β-, Notch-, and Wnt-Mediated EMT.

Zoni E, van der Pluijm G, Gray PC, Kruithof-de Julio M - J Oncol (2015)

Bottom Line: Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT.In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways.Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

ABSTRACT
Epithelial-to-mesenchymal transition (EMT) is a reversible process by which cancer cells can switch from a sessile epithelial phenotype to an invasive mesenchymal state. EMT enables tumor cells to become invasive, intravasate, survive in the circulation, extravasate, and colonize distant sites. Paracrine heterotypic stroma-derived signals as well as paracrine homotypic or autocrine signals can mediate oncogenic EMT and contribute to the acquisition of stem/progenitor cell properties, expansion of cancer stem cells, development of therapy resistance, and often lethal metastatic disease. EMT is regulated by a variety of stimuli that trigger specific intracellular signalling pathways. Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT. In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways. Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

No MeSH data available.


Related in: MedlinePlus

Venn diagram showing number of overlapping KEGG pathway genes from the TGF-β, Wnt, and Notch pathways.
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fig2: Venn diagram showing number of overlapping KEGG pathway genes from the TGF-β, Wnt, and Notch pathways.

Mentions: DIANA-miRPath was used to collect the complete list of manually annotated, experimentally validated, and published target genes for the 30 miRs identified. This was done in order to get better insight into the experimental data and understand the functional relevance of our analysis. Of all validated target genes 48 genes could be ascribed to the TGF-β pathway (P value = 6.9e − 09), 30 to the Notch pathway (P value = 4.7e − 05), and 88 to the Wnt signalling pathway (P value = 5.07e − 14). Using the same approach as for the miRs, a cluster of genes was found to be shared between only two of the three pathways (i.e., experimentally validated miR-gene interactions from TGF-β and Notch, TGF-β and Wnt, or Notch and Wnt KEGG pathways). With this procedure, we identified 8 manually annotated and validated target genes shared by TGF-β and Wnt KEGG pathways (SMAD2, SMAD3, SMAD4, ROCK2, RHOA, MYC, PPP2R1A, and PPP2R1B) and 5 manually annotated and validated target genes shared by Notch and Wnt KEGG pathways (CTBP1, CTBP2, DVL2, DVL3, and PSEN1). Interestingly, no genes were shared between TGF-β and Notch KEGG pathways (Figure 2). Finally, we determined whether a new cluster of experimentally validated target genes coupled to our signature described above could be connected to a common biological process among TGF-β, Notch, and Wnt signalling pathways. Strikingly, only 2 validated target genes, the transcriptional coactivator cAMP-response element-binding protein- (CREB-) binding protein (CBP) and the adenovirus E1A-associated cellular p300 transcriptional coactivator protein p300 (EP300), were shared exclusively between the TGF-β, Notch, and Wnt signalling KEGG pathways (Figure 2). These results indicate the relevance of the 30-identified-miR signature thus suggesting a possible link between these miRs and cross talk between TGF-β, Notch, and Wnt pathways during EMT.


Epithelial Plasticity in Cancer: Unmasking a MicroRNA Network for TGF-β-, Notch-, and Wnt-Mediated EMT.

Zoni E, van der Pluijm G, Gray PC, Kruithof-de Julio M - J Oncol (2015)

Venn diagram showing number of overlapping KEGG pathway genes from the TGF-β, Wnt, and Notch pathways.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4390187&req=5

fig2: Venn diagram showing number of overlapping KEGG pathway genes from the TGF-β, Wnt, and Notch pathways.
Mentions: DIANA-miRPath was used to collect the complete list of manually annotated, experimentally validated, and published target genes for the 30 miRs identified. This was done in order to get better insight into the experimental data and understand the functional relevance of our analysis. Of all validated target genes 48 genes could be ascribed to the TGF-β pathway (P value = 6.9e − 09), 30 to the Notch pathway (P value = 4.7e − 05), and 88 to the Wnt signalling pathway (P value = 5.07e − 14). Using the same approach as for the miRs, a cluster of genes was found to be shared between only two of the three pathways (i.e., experimentally validated miR-gene interactions from TGF-β and Notch, TGF-β and Wnt, or Notch and Wnt KEGG pathways). With this procedure, we identified 8 manually annotated and validated target genes shared by TGF-β and Wnt KEGG pathways (SMAD2, SMAD3, SMAD4, ROCK2, RHOA, MYC, PPP2R1A, and PPP2R1B) and 5 manually annotated and validated target genes shared by Notch and Wnt KEGG pathways (CTBP1, CTBP2, DVL2, DVL3, and PSEN1). Interestingly, no genes were shared between TGF-β and Notch KEGG pathways (Figure 2). Finally, we determined whether a new cluster of experimentally validated target genes coupled to our signature described above could be connected to a common biological process among TGF-β, Notch, and Wnt signalling pathways. Strikingly, only 2 validated target genes, the transcriptional coactivator cAMP-response element-binding protein- (CREB-) binding protein (CBP) and the adenovirus E1A-associated cellular p300 transcriptional coactivator protein p300 (EP300), were shared exclusively between the TGF-β, Notch, and Wnt signalling KEGG pathways (Figure 2). These results indicate the relevance of the 30-identified-miR signature thus suggesting a possible link between these miRs and cross talk between TGF-β, Notch, and Wnt pathways during EMT.

Bottom Line: Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT.In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways.Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

ABSTRACT
Epithelial-to-mesenchymal transition (EMT) is a reversible process by which cancer cells can switch from a sessile epithelial phenotype to an invasive mesenchymal state. EMT enables tumor cells to become invasive, intravasate, survive in the circulation, extravasate, and colonize distant sites. Paracrine heterotypic stroma-derived signals as well as paracrine homotypic or autocrine signals can mediate oncogenic EMT and contribute to the acquisition of stem/progenitor cell properties, expansion of cancer stem cells, development of therapy resistance, and often lethal metastatic disease. EMT is regulated by a variety of stimuli that trigger specific intracellular signalling pathways. Altered microRNA (miR) expression and perturbed signalling pathways have been associated with epithelial plasticity, including oncogenic EMT. In this review we analyse and describe the interaction between experimentally validated miRs and their target genes in TGF-β, Notch, and Wnt signalling pathways. Interestingly, in this process, we identified a "signature" of 30 experimentally validated miRs and a cluster of validated target genes that seem to mediate the cross talk between TGF-β, Notch, and Wnt signalling networks during EMT and reinforce their connection to the regulation of epithelial plasticity in health and disease.

No MeSH data available.


Related in: MedlinePlus