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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

The TGF-β/ZEB/miR-200 regulatory network.
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Related In: Results  -  Collection


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fig2: The TGF-β/ZEB/miR-200 regulatory network.

Mentions: Gregory et al. recently demonstrated the existence of an autocrine TGF-β/ZEB/miR-200 signaling regulatory network that controls the plasticity between the epithelial and mesenchymal states of the cells. Strong correlation was reported between the ZEB1/2 and TGF-β and negative correlations were detected between miR-200 and TGF-β, as well as between miR-200 and ZEB1/2, in invasive ductal carcinomas [68]. ZEB1/2 can induce EMT by repressing various epithelial genes [69]. The TGF-β signaling pathway is a central activator of ZEB1/2, indicating that they are important intracellular mediators of the TGF-β-induced EMT. The crosstalk between the ZEB/miR-200 axis and several signal transduction pathways activated at different stages of tumor development was also reviewed recently [70]. ZEB1/2 and the miR-200 family are involved in a double-negative feedback loop, which controls EMT and MET programs both in development and tumorigenesis [70]. On one hand, the miR-200 members target and suppress ZEB1/2 and promote epithelial differentiation [64, 71, 72]. On the other hand, ZEB1 knockdown can enhance miR-200 [73] (Figure 2). This was supported when it was found that the common promoter region of the miR-200 members includes highly conserved ZEB-binding sites, through which ZEB factors control the transcription of the miR-200 family [73, 74]. ZEB downregulation leads to the enhancement of an epithelial pattern of gene expression through induction of the miR-200 members. On the contrary, ZEB expression induces a mesenchymal pattern of gene expression through miR-200 suppression. This feedback loop was shown to play important roles in the stabilization of cellular differentiation in response to prevalent extracellular cues [75]. In gastric cancer, miR-200b can control metastasis by regulating the expression of ZEB2 [76]. Cong et al. found inversely related expression levels between miR-200a and ZEB1/2 in gastric adenocarcinoma tissue arrays. The upregulated miR-200a expression was also found to increase E-cadherin and suppress the Wnt/β-catenin pathway by targeting ZEB1/2 in gastric adenocarcinoma, thus delaying tumor growth in vivo [77].


The Regulatory Role of MicroRNAs in EMT and Cancer.

Zaravinos A - J Oncol (2015)

The TGF-β/ZEB/miR-200 regulatory network.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: The TGF-β/ZEB/miR-200 regulatory network.
Mentions: Gregory et al. recently demonstrated the existence of an autocrine TGF-β/ZEB/miR-200 signaling regulatory network that controls the plasticity between the epithelial and mesenchymal states of the cells. Strong correlation was reported between the ZEB1/2 and TGF-β and negative correlations were detected between miR-200 and TGF-β, as well as between miR-200 and ZEB1/2, in invasive ductal carcinomas [68]. ZEB1/2 can induce EMT by repressing various epithelial genes [69]. The TGF-β signaling pathway is a central activator of ZEB1/2, indicating that they are important intracellular mediators of the TGF-β-induced EMT. The crosstalk between the ZEB/miR-200 axis and several signal transduction pathways activated at different stages of tumor development was also reviewed recently [70]. ZEB1/2 and the miR-200 family are involved in a double-negative feedback loop, which controls EMT and MET programs both in development and tumorigenesis [70]. On one hand, the miR-200 members target and suppress ZEB1/2 and promote epithelial differentiation [64, 71, 72]. On the other hand, ZEB1 knockdown can enhance miR-200 [73] (Figure 2). This was supported when it was found that the common promoter region of the miR-200 members includes highly conserved ZEB-binding sites, through which ZEB factors control the transcription of the miR-200 family [73, 74]. ZEB downregulation leads to the enhancement of an epithelial pattern of gene expression through induction of the miR-200 members. On the contrary, ZEB expression induces a mesenchymal pattern of gene expression through miR-200 suppression. This feedback loop was shown to play important roles in the stabilization of cellular differentiation in response to prevalent extracellular cues [75]. In gastric cancer, miR-200b can control metastasis by regulating the expression of ZEB2 [76]. Cong et al. found inversely related expression levels between miR-200a and ZEB1/2 in gastric adenocarcinoma tissue arrays. The upregulated miR-200a expression was also found to increase E-cadherin and suppress the Wnt/β-catenin pathway by targeting ZEB1/2 in gastric adenocarcinoma, thus delaying tumor growth in vivo [77].

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