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      Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer

      review-article
      ,   *
      Molecules
      MDPI
      epithelial–mesenchymal transition, drug resistance, chemotherapy, cancer stem cells

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          Abstract

          Epithelial–mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance.

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          Most cited references69

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          Identification of selective inhibitors of cancer stem cells by high-throughput screening.

          Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
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            Epithelial-mesenchymal transitions in development and pathologies.

            The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
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              The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.

              Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. Here, we report that expression of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter. SIP1 and Snail bind to partly overlapping promoter sequences and showed similar silencing effects. SIP1 can be induced by TGF-beta treatment and shows high expression in several E-cadherin-negative human carcinoma cell lines. Conditional expression of SIP1 in E-cadherin-positive MDCK cells abrogates E-cadherin-mediated intercellular adhesion and simultaneously induces invasion. SIP1 therefore appears to be a promoter of invasion in malignant epithelial tumors.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                22 July 2016
                July 2016
                : 21
                : 7
                : 965
                Affiliations
                Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR 999078, China; dbw@ 123456mail.ustc.edu.cn
                Author notes
                [* ]Correspondence: jsshim@ 123456umac.mo ; Tel.: +853-8822-4990
                Article
                molecules-21-00965
                10.3390/molecules21070965
                6273543
                27455225
                c01df5d1-6917-4cca-8f1b-703f3b90f422
                © 2016 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 June 2016
                : 19 July 2016
                Categories
                Review

                epithelial–mesenchymal transition,drug resistance,chemotherapy,cancer stem cells

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