Interplay Between Transcription Factors and MicroRNAs Regulating Epithelial-Mesenchymal Transitions in Colorectal Cancer
The epithelial-mesenchymal-transition (EMT) represents a morphogenetic program involved in developmental processes such as gastrulation and neural crest formation. The EMT program is co-opted by epithelial tumor cells and endows them with features necessa
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Interplay Between Transcription Factors and MicroRNAs Regulating Epithelial-Mesenchymal Transitions in Colorectal Cancer Markus Kaller and Heiko Hermeking
Abstract
The epithelial-mesenchymal-transition (EMT) represents a morphogenetic program involved in developmental processes such as gastrulation and neural crest formation. The EMT program is co-opted by epithelial tumor cells and endows them with features necessary for spreading to distant sites, such as invasion, migration, apoptosis resistance and stemness. Thereby, EMT facilitates metastasis formation and therapy resistance. A growing number of transcription factors has been implicated in the regulation of EMT. These include EMT-inducing transcription factors (EMTTFs), the most prominent being SNAIL, SLUG, ZEB1, ZEB2 and TWIST, and negative regulators of EMT, such as p53. Furthermore, a growing number of microRNAs, such as members of the miR-200 and miR-34 family, have been characterized as negative regulators of EMT. EMT-TFs and microRNAs, such as ZEB1/2 and miR-200 or SNAIL and miR-34, are often engaged in double-negative feedback loops forming bistable switches controlling the transitions from epithelial to the mesenchymal cell states. Within this chapter, we will provide a comprehensive overview over the transcription factors and microRNAs that have been implicated in the regulation of EMT in colorectal cancer. Furthermore, we will highlight the regulatory connections between EMT-TFs and miRNAs to illustrate common principles of their interaction that regulate EMTs.
H. Hermeking (*) Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Thalkirchner Strasse 36, 80337 Munich, Germany
M. Kaller Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Thalkirchner Strasse 36, 80337 Munich, Germany
German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany e-mail: [email protected]
© Springer International Publishing Switzerland 2016 O. Slaby, G.A. Calin (eds.), Non-coding RNAs in Colorectal Cancer, Advances in Experimental Medicine and Biology 937, DOI 10.1007/978-3-319-42059-2_4
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M. Kaller and H. Hermeking
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Keywords
miR-34 • p53 • c-MYC • Metastasis • EMT
4.1
Introduction
The ability to metastasize represents an important feature of cancer cells [1]. Whereas surgical resection and adjuvant therapy can cure spatially restricted primary tumors, metastatic disease is largely incurable because of its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents (reviewed in [2]). This explains why > 90 % of mortality from cancer is attributable to metastases, and not to the primary tumors from which these malignant lesions arise [3, 4]. The term “epithelial-mesenchymal transition” describes a cellular transdifferentiation program that is employed during embryogenic developmental stages such as gastrulation and neural crest formation, as wel
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