A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

doi:10.1038/EMBOR.2008.74

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A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

Journal Article•DOI•

A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

Ulrike Burk¹, Joerg Schubert¹, Ulrich F. Wellner¹, Otto Schmalhofer¹, Elizabeth Vincan², Simone Spaderna¹, Thomas Brabletz¹ - Show less +3 more•Institutions (2)

University of Freiburg¹, University of Melbourne²

01 Jun 2008-EMBO Reports (John Wiley & Sons, Ltd)-Vol. 9, Iss: 6, pp 582-589

TL;DR: Results indicate that ZEB1 triggers an microRNA‐mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells, and thus explain the strong intratumorous heterogeneity observed in many human cancers.

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Abstract: The embryonic programme 'epithelial-mesenchymal transition' (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA-200 family members miR-141 and miR-200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor beta2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA-mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers.

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Journal Article•DOI•

Epithelial-Mesenchymal Transitions in Development and Disease

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Jean Paul Thiery¹, Jean Paul Thiery², Hervé Acloque³, Ruby Yun-Ju Huang¹, Ruby Yun-Ju Huang², M. Angela Nieto³ - Show less +2 more•Institutions (3)

Agency for Science, Technology and Research¹, National University of Singapore², Spanish National Research Council³

25 Nov 2009-Cell

TL;DR: The mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.

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8,642 citations

Cites background from "A reciprocal repression between ZEB..."

...…Snail1) can bind to the promoters of miR-141 and -200c and suppress their expression, thereby generating a regulatory loop that can reinforce the ability of Zeb1 to maintain a stable mesenchymal phenotype, as observed at the invasive front of colon carcinoma cells (Burk et al., 2008) (Figure 4)....
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...This hypothesis has recently been validated as Zeb1 (and probably Snail1) can bind to the promoters of miR-141 and -200c and suppress their expression, thereby generating a regulatory loop that can reinforce the ability of Zeb1 to maintain a stable mesenchymal phenotype, as observed at the invasive front of colon carcinoma cells (Burk et al., 2008) (Figure 4)....
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Journal Article•DOI•

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

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Rajesha Rupaimoole¹, Frank J. Slack¹•Institutions (1)

Beth Israel Deaconess Medical Center¹

01 Mar 2017-Nature Reviews Drug Discovery

TL;DR: Recent advances in the understanding of miRNAs in cancer and in other diseases are described and the challenge of identifying the most efficacious therapeutic candidates is discussed and a perspective on achieving safe and targeted delivery of miRNA therapeutics is provided.

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Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

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3,210 citations

Journal Article•DOI•

EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer

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Anurag K. Singh¹, Jeffrey Settleman¹•Institutions (1)

Harvard University¹

26 Aug 2010-Oncogene

TL;DR: This review will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs, and highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal.

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Abstract: Tumors are cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like features (CSCs). Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs that are required for tissue morphogenesis during embryonic development. The EMT process can be regulated by a diverse array of cytokines and growth factors, such as transforming growth factor (TGF)-β, whose activities are dysregulated during malignant tumor progression. Thus, EMT induction in cancer cells results in the acquisition of invasive and metastatic properties. Recent reports indicate that the emergence of CSCs occurs in part as a result of EMT, for example, through cues from tumor stromal components. Recent evidence now indicates that EMT of tumor cells not only causes increased metastasis, but also contributes to drug resistance. In this review, we will provide potential mechanistic explanations for the association between EMT induction and the emergence of CSCs. We will also highlight recent studies implicating the function of TGF-β-regulated noncoding RNAs in driving EMT and promoting CSC self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug resistance, as well as therapeutic strategies to overcome this clinically.

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2,342 citations

Cites background from "A reciprocal repression between ZEB..."

...Most significantly, EMT is regulated by the expression of the mir-200 family and mir-205 (Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008; Park et al., 2008)....
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Journal Article•DOI•

Regulatory networks defining EMT during cancer initiation and progression

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Bram De Craene¹, Geert Berx¹•Institutions (1)

Ghent University¹

01 Feb 2013-Nature Reviews Cancer

TL;DR: The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them.

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Abstract: Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

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2,136 citations

Journal Article•DOI•

MicroRNAs in cancer.

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Gianpiero Di Leva¹, Michela Garofalo, Carlo M. Croce¹•Institutions (1)

Ohio State University¹

24 Jan 2014-Annual Review of Pathology-mechanisms of Disease

TL;DR: In this paper, the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies are discussed.

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Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.

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1,899 citations

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References

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Journal Article•DOI•

MicroRNAs: Genomics, Biogenesis, Mechanism, and Function

[...]

David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

23 Jan 2004-Cell

TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

...read moreread less

32,946 citations

"A reciprocal repression between ZEB..." refers background in this paper

...MicroRNAs (miRNAs) are small non-coding RNAs that can silence their cognate target genes by specifically binding and cleaving messenger RNAs or inhibiting their translation (Bartel, 2004)....
[...]
...…non-coding RNAs that can silence their cognate target genes by specifically binding and cleaving messenger RNAs or inhibiting their translation (Bartel, 2004). miRNAs regulate diverse cellular processes and some miRNAs have been shown to function as either tumour suppressors or oncogenes…...
[...]

Journal Article•

Oncomirs : microRNAs with a role in cancer

[...]

Aurora Esquela-Kerscher, Frank J. Slack

01 Jan 2007-Nature Reviews Genetics

TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.

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Abstract: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.

...read moreread less

6,064 citations

Journal Article•DOI•

Prediction of Mammalian MicroRNA Targets

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Benjamin P. Lewis¹, I-hung Shih¹, Matthew W. Jones-Rhoades¹, David P. Bartel¹, Christopher B. Burge¹ - Show less +1 more•Institutions (1)

Massachusetts Institute of Technology¹

26 Dec 2003-Cell

TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.

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5,246 citations

"A reciprocal repression between ZEB..." refers methods in this paper

...To explain further the mechanisms by which both miRNAs induce epithelial differentiation, we searched for putative target genes on the basis of the predicted mRNA recognition sequence of the conserved stem–loop sequences by using the TargetScan search programme ( Lewis et al, 2003 )....
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...To explain further the mechanisms by which both miRNAs induce epithelial differentiation, we searched for putative target genes on the basis of the predicted mRNA recognition sequence of the conserved stem–loop sequences by using the TargetScan search programme (Lewis et al, 2003)....
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Journal Article•DOI•

Complex networks orchestrate epithelial–mesenchymal transitions

[...]

Jean Paul Thiery¹, Jonathan P. Sleeman²•Institutions (2)

Centre national de la recherche scientifique¹, Karlsruhe Institute of Technology²

01 Feb 2006-Nature Reviews Molecular Cell Biology

TL;DR: Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.

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Abstract: Epithelial-mesenchymal transition is an indispensable mechanism during morphogenesis, as without mesenchymal cells, tissues and organs will never be formed. However, epithelial-cell plasticity, coupled to the transient or permanent formation of mesenchyme, goes far beyond the problem of cell-lineage segregation. Understanding how mesenchymal cells arise from an epithelial default status will also have a strong impact in unravelling the mechanisms that control fibrosis and cancer progression.

...read moreread less

3,804 citations

"A reciprocal repression between ZEB..." refers background in this paper

...EMBO open A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells...
[...]
...Activators of EMT, such as transforming growth factor (TGF)b, tumour necrosis factor a (TNFa) and hepatocyte growth factor, are produced by infiltrating cells or the tumour cells themselves, and trigger expression of EMT-inducing transcriptional repressors (Thiery & Sleeman, 2006)....
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Journal Article•DOI•

Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis

[...]

Jing Yang¹, Sendurai A. Mani¹, Joana Liu Donaher¹, Sridhar Ramaswamy², Sridhar Ramaswamy³, Raphael Itzykson⁴, Christophe Côme⁵, Pierre Savagner⁵, Inna Gitelman⁶, Andrea L. Richardson³, Robert A. Weinberg¹ - Show less +7 more•Institutions (6)

Massachusetts Institute of Technology¹, Broad Institute², Harvard University³, École Normale Supérieure⁴, French Institute of Health and Medical Research⁵, Ben-Gurion University of the Negev⁶

25 Jun 2004-Cell

TL;DR: A mechanistic link between Twist, EMT, and tumor metastasis is established, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT).

...read moreread less

3,670 citations

"A reciprocal repression between ZEB..." refers background in this paper

...In the light of the important role of ZEB1 and other EMT inducers, such as Snail (Olmeda et al, 2007), Twist ( Yang et al, 2004 ) and of EMT as a whole in tumour progression, our data, indicating that ZEB1 promotes an EMT-stabilizing feedforward loop by suppressing specific miRNAs, add functional evidence for the molecular mechanisms underlying these processes....
[...]
...In the light of the important role of ZEB1 and other EMT inducers, such as Snail (Olmeda et al, 2007), Twist (Yang et al, 2004) and of EMT as a whole in tumour progression, our data, indicating that ZEB1 promotes an EMT-stabilizing feedforward loop by suppressing specific miRNAs, add functional evidence for the molecular mechanisms underlying these processes....
[...]
...In the light of the important role of ZEB1 and other EMT inducers, such as Snail (Olmeda et al, 2007), Twist (Yang et al, 2004) and of EMT as a whole in tumour progression, our data, indicating that ZEB1 promotes an EMT-stabilizing feedforward loop by suppressing specific miRNAs, add functional…...
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