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      Reactive oxygen species promote ovarian cancer progression via the HIF-1α/LOX/E-cadherin pathway

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          Abstract

          Reactive oxygen species (ROS) can drive the de-differentiation of tumor cells leading to the process of epithelial-to-mesenchymal transition (EMT) to enhance invasion and metastasis. The invasive and metastatic phenotype of malignant cells is often linked to loss of E-cadherin expression, a hallmark of EMT. Recent studies have demonstrated that hypoxic exposure causes HIF-1-dependent repression of E-cadherin. However, the mechanism by which ROS and/or HIF suppresses E-cadherin expression remains less clear. In the present study, we found that ROS accumulation in ovarian carcinoma cells upregulated HIF-1α expression and subsequent transcriptional induction of lysyl oxidase (LOX) which repressed E-cadherin. Loss of E-cadherin facilitated ovarian cancer (OC) cell migration in vitro and promoted tumor growth in vivo. E-cadherin immunoreactivity correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, tumor differentiation and metastasis. Negative E-cadherin expression along with FIGO stage, tumor differentiation and metastasis significantly predicted for a lower 5-year survival rate. These findings suggest that ROS play an important role in the initiation of metastatic growth of OC cells and support a molecular pathway from ROS to aggressive transformation which involves upregulation of HIF-1α and its downstream target LOX to suppress E-cadherin expression leading to an increase in cell motility and invasiveness.

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          Most cited references30

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          Microenvironmental regulation of metastasis.

          Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
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            Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.

            Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.
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              Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell.

              Lysyl oxidase (LO) plays a critical role in the formation and repair of the extracellular matrix (ECM) by oxidizing lysine residues in elastin and collagen, thereby initiating the formation of covalent crosslinkages which stabilize these fibrous proteins. Its catalytic activity depends upon both its copper cofactor and a unique carbonyl cofactor and has been shown to extend to a variety of basic globular proteins, including histone H1. Although the three-dimensional structure of LO has yet to be determined, the present treatise offers hypotheses based upon its primary sequence, which may underlie the prominent electrostatic component of its unusual substrate specificity as well as the catalysis-suppressing function of the propeptide domain of prolysyl oxidase. Recent studies have demonstrated that LO appears to function within the cell in a manner, which strongly modifies cellular activity. Newly discovered LO-like proteins also likely play unique roles in biology. Copyright 2002 Wiley-Liss, Inc.
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                Author and article information

                Journal
                Oncol Rep
                Oncol. Rep
                Oncology Reports
                D.A. Spandidos
                1021-335X
                1791-2431
                November 2014
                28 August 2014
                : 32
                : 5
                : 2150-2158
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
                [2 ]Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China
                [3 ]Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA
                Author notes
                Correspondence to: Dr Yu Wang, Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, P.R. China, E-mail: wangyuxinjian@ 123456gmail.com . Dr Xinjian Lin, Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA, E-mail: xlin@ 123456ucsd.edu
                Article
                or-32-05-2150
                10.3892/or.2014.3448
                4440217
                25174950
                318b54a9-1aff-4ffb-8d08-1a00cdc99e8c
                Copyright © 2014, Spandidos Publications

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 17 June 2014
                : 12 August 2014
                Categories
                Articles

                reactive oxygen species,hypoxia-inducible transcription factor-1,lysyl oxidase,e-cadherin,ovarian carcinomas

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