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      EMT Factors and Metabolic Pathways in Cancer


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          The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

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          Most cited references211

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          p53 mutations in human cancers

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            miR-21-mediated tumor growth.

            MicroRNAs (miRNAs) are approximately 22 nucleotide non-coding RNA molecules that regulate gene expression post-transcriptionally. Although aberrant expression of miRNAs in various human cancers suggests a role for miRNAs in tumorigenesis, it remains largely unclear as to whether knockdown of a specific miRNA affects tumor growth. In this study, we profiled miRNA expression in matched normal breast tissue and breast tumor tissues by TaqMan real-time polymerase chain reaction miRNA array methods. Consistent with previous findings, we found that miR-21 was highly overexpressed in breast tumors compared to the matched normal breast tissues among 157 human miRNAs analysed. To better evaluate the role of miR-21 in tumorigenesis, we transfected breast cancer MCF-7 cells with anti-miR-21 oligonucleotides and found that anti-miR-21 suppressed both cell growth in vitro and tumor growth in the xenograft mouse model. Furthermore, this anti-miR-21-mediated cell growth inhibition was associated with increased apoptosis and decreased cell proliferation, which could be in part owing to downregulation of the antiapoptotic Bcl-2 in anti-miR-21-treated tumor cells. Together, these results suggest that miR-21 functions as an oncogene and modulates tumorigenesis through regulation of genes such as bcl-2 and thus, it may serve as a novel therapeutic target.
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              Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.

              The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGFβ. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential. Copyright © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                07 April 2020
                : 10
                : 499
                [1] 1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco , San Francisco, CA, United States
                [2] 2Institute for Human Genetics, University of California, San Francisco , San Francisco, CA, United States
                [3] 3Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne , Lausanne, Switzerland
                [4] 4Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras , Patras, Greece
                [5] 5College of Medicine, Member of QU Health, Qatar University , Doha, Qatar
                [6] 6Department of Life Sciences European University Cyprus , Nicosia, Cyprus
                Author notes

                Edited by: Katarína Smolková, Institute of Physiology (ASCR), Czechia

                Reviewed by: Joanna Maria Boncela, Institute for Medical Biology (PAN), Poland; Dongya Jia, Rice University, United States; Andre Koit, National Institute of Chemical Physics and Biophysics, Estonia

                *Correspondence: Apostolos Zaravinos azaravinos@ 123456qu.edu.qa

                This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology

                Copyright © 2020 Georgakopoulos-Soares, Chartoumpekis, Kyriazopoulou and Zaravinos.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 07 January 2020
                : 19 March 2020
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 315, Pages: 20, Words: 18001

                Oncology & Radiotherapy
                emt,metabolic pathways,transcription factors,non-coding rnas,cancer metabolism


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