Limits...
The Regulatory Role of MicroRNAs in EMT and Cancer.

Zaravinos A - J Oncol (2015)

Bottom Line: The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated.The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed.Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet Huddinge, 171 77 Stockholm, Sweden.

ABSTRACT
The epithelial to mesenchymal transition (EMT) is a powerful process in tumor invasion, metastasis, and tumorigenesis and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells. It is now well known that miRNAs are important regulators of malignant transformation and metastasis. The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated. The metastasis suppressive role of the miR-200 members is strongly associated with a pathologic EMT. This review describes the most recent advances regarding the influence of miRNAs in EMT and the control they exert in major signaling pathways in various cancers. The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed. Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways. The link between cancer stem cells and EMT is also reported and the most recent developments regarding clinical trials that are currently using anti-miRNA constructs are further discussed.

No MeSH data available.


Related in: MedlinePlus

Major interconnected signaling pathways that regulate EMT. The Smad pathway for TGF-β signaling acts through the formation of a complex between Smad 2/3 and Smad 4. The complex then moves to the nucleus and stimulates the transcription of target genes. Sharp arrows denote activation/upregulation and blunt arrows denote inhibition/downregulation. Fz: frizzled receptors; Gli: glioma-associated oncogene family of transcription factors; GSK-3b: glycogen synthase kinase; Hh: hedgehog; PI3K: phosphatidylinositol-3-kinase; ILK: integrin-linked kinase; LRP: low-density lipoprotein receptor-related protein; p38 MAPK: mitogen-activated protein kinase; Ptc: patched receptor for Hh signaling; SMO: smoothened; TGF-β: transforming growth factor β; uPAR: urokinase plasminogen activator receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4389820&req=5

fig1: Major interconnected signaling pathways that regulate EMT. The Smad pathway for TGF-β signaling acts through the formation of a complex between Smad 2/3 and Smad 4. The complex then moves to the nucleus and stimulates the transcription of target genes. Sharp arrows denote activation/upregulation and blunt arrows denote inhibition/downregulation. Fz: frizzled receptors; Gli: glioma-associated oncogene family of transcription factors; GSK-3b: glycogen synthase kinase; Hh: hedgehog; PI3K: phosphatidylinositol-3-kinase; ILK: integrin-linked kinase; LRP: low-density lipoprotein receptor-related protein; p38 MAPK: mitogen-activated protein kinase; Ptc: patched receptor for Hh signaling; SMO: smoothened; TGF-β: transforming growth factor β; uPAR: urokinase plasminogen activator receptor.

Mentions: Various signaling pathways can induce EMT and include key molecules such as transforming growth factor beta (TGF-β), growth factors that act through tyrosine kinase receptors (RTKs), like platelet-derived growth factor (PDGF) and fibroblast growth factor receptors (FGFRs) [4, 9], and the proteins nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Wnt (wingless integrated), and Notch and hedgehog (Hh) proteins [10] (Figure 1). These signaling pathways stimulate transcription factors like Snail, basic helix-loop-helix (bHLH), zinc finger E-box-binding homeobox1/2 (ZEB1/2), and NF-κB, among others, that repress epithelial gene expression and act as activators of EMT [11]. These proteins bind to the promoter of E-cadherin silencing its expression. E-cadherin is a central component of the adherens junction complex, responsible for the calcium-dependent cell-cell adhesion and the maintenance of the cytoskeletal organization. Its loss is a causal factor in cancer progression. Transcriptional repression of E-cadherin is an important emerging mechanism through which the gene is downregulated during tumor progression and several transcription factors, among them Snail, Slug/Snail2, ZEB1, ZEB2, and E47, directly bind to its promoter and repress its transcription. EMT is induced through various channels. Many of these E-cadherin repressors are induced by the stimulation of the TGF-β pathway and they can further repress the transcription of other cell polarity and adhesion genes [12] (Figure 1).


The Regulatory Role of MicroRNAs in EMT and Cancer.

Zaravinos A - J Oncol (2015)

Major interconnected signaling pathways that regulate EMT. The Smad pathway for TGF-β signaling acts through the formation of a complex between Smad 2/3 and Smad 4. The complex then moves to the nucleus and stimulates the transcription of target genes. Sharp arrows denote activation/upregulation and blunt arrows denote inhibition/downregulation. Fz: frizzled receptors; Gli: glioma-associated oncogene family of transcription factors; GSK-3b: glycogen synthase kinase; Hh: hedgehog; PI3K: phosphatidylinositol-3-kinase; ILK: integrin-linked kinase; LRP: low-density lipoprotein receptor-related protein; p38 MAPK: mitogen-activated protein kinase; Ptc: patched receptor for Hh signaling; SMO: smoothened; TGF-β: transforming growth factor β; uPAR: urokinase plasminogen activator receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4389820&req=5

fig1: Major interconnected signaling pathways that regulate EMT. The Smad pathway for TGF-β signaling acts through the formation of a complex between Smad 2/3 and Smad 4. The complex then moves to the nucleus and stimulates the transcription of target genes. Sharp arrows denote activation/upregulation and blunt arrows denote inhibition/downregulation. Fz: frizzled receptors; Gli: glioma-associated oncogene family of transcription factors; GSK-3b: glycogen synthase kinase; Hh: hedgehog; PI3K: phosphatidylinositol-3-kinase; ILK: integrin-linked kinase; LRP: low-density lipoprotein receptor-related protein; p38 MAPK: mitogen-activated protein kinase; Ptc: patched receptor for Hh signaling; SMO: smoothened; TGF-β: transforming growth factor β; uPAR: urokinase plasminogen activator receptor.
Mentions: Various signaling pathways can induce EMT and include key molecules such as transforming growth factor beta (TGF-β), growth factors that act through tyrosine kinase receptors (RTKs), like platelet-derived growth factor (PDGF) and fibroblast growth factor receptors (FGFRs) [4, 9], and the proteins nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Wnt (wingless integrated), and Notch and hedgehog (Hh) proteins [10] (Figure 1). These signaling pathways stimulate transcription factors like Snail, basic helix-loop-helix (bHLH), zinc finger E-box-binding homeobox1/2 (ZEB1/2), and NF-κB, among others, that repress epithelial gene expression and act as activators of EMT [11]. These proteins bind to the promoter of E-cadherin silencing its expression. E-cadherin is a central component of the adherens junction complex, responsible for the calcium-dependent cell-cell adhesion and the maintenance of the cytoskeletal organization. Its loss is a causal factor in cancer progression. Transcriptional repression of E-cadherin is an important emerging mechanism through which the gene is downregulated during tumor progression and several transcription factors, among them Snail, Slug/Snail2, ZEB1, ZEB2, and E47, directly bind to its promoter and repress its transcription. EMT is induced through various channels. Many of these E-cadherin repressors are induced by the stimulation of the TGF-β pathway and they can further repress the transcription of other cell polarity and adhesion genes [12] (Figure 1).

Bottom Line: The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated.The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed.Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet Huddinge, 171 77 Stockholm, Sweden.

ABSTRACT
The epithelial to mesenchymal transition (EMT) is a powerful process in tumor invasion, metastasis, and tumorigenesis and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells. It is now well known that miRNAs are important regulators of malignant transformation and metastasis. The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated. The metastasis suppressive role of the miR-200 members is strongly associated with a pathologic EMT. This review describes the most recent advances regarding the influence of miRNAs in EMT and the control they exert in major signaling pathways in various cancers. The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed. Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways. The link between cancer stem cells and EMT is also reported and the most recent developments regarding clinical trials that are currently using anti-miRNA constructs are further discussed.

No MeSH data available.


Related in: MedlinePlus