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      FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway

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          Abstract

          Gastric cancer (GC), characterized by uncontrolled growth, is a common malignant tumor of the digestive system. The Wnt signaling pathway plays an important role in the tumorigenesis and proliferation of GC. Many studies on this signaling pathway have focused on its intracellular regulatory mechanism, whereas little attention has been given to extracellular regulatory factors. Dickkopf-1 (Dkk1) is a secretory glycoprotein, and it can bind inhibit activation of the Wnt pathway. However, the regulation and mechanism of DKK1 in the proliferation of GC remain unclear. FOXC1 plays an important role in organ development and tumor growth, but its role in GC tumor growth remains unknown. In this study, we found that the FOXC1 is highly expressed in patients with GC and high expression of FOXC1 correlates to poor prognosis. In addition, we found that the Wnt signaling pathway in GC cells with high FOXC1 expression was strongly activated. FOXC1 negatively regulates DKK1 expression by binding to its promoter region, thereby promoting the activation of Wnt pathway. FOXC1 can also form a complex with unphosphorylated β-catenin protein in the cytoplasm and then dissociates from β-catenin in the nucleus, thereby promoting the entry of β-catenin into the nucleus and regulating expression of c-MYC, which promotes the proliferation of GC cells. Our study not only reveals the function and mechanism of FOXC1 in GC, but also provides a potential target for clinic GC treatment.

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          Most cited references39

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          Wnt/β-catenin signaling and disease.

          The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Wnt signaling in cancer

            Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.
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              The Global Burden of Cancer 2013

              Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                27 April 2021
                2021
                : 9
                : 662624
                Affiliations
                [1] 1Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [2] 2Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [3] 3Department of Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [4] 4Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [5] 5Department of Ocular Fundus Diseases, Shanxi Eye Hospital , Shanxi, China
                Author notes

                Edited by: Elizabeth Lara Ostler, University of Brighton, United Kingdom

                Reviewed by: Toby Phesse, Cardiff University, United Kingdom; YangXin Fu, University of Alberta, Canada

                *Correspondence: Fei Yuan, daphny2014@ 123456163.com

                These authors have contributed equally to this work and share first authorship

                This article was submitted to Cell Growth and Division, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2021.662624
                8111291
                33987183
                7c35564e-1533-466b-ae91-a39a070652d9
                Copyright © 2021 Jiang, Li, Yao, Wang, Shi, Yuan, Dong and Zhang.

                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.

                History
                : 01 February 2021
                : 29 March 2021
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 39, Pages: 14, Words: 0
                Categories
                Cell and Developmental Biology
                Original Research

                gastric cancer,foxc1,dkk1,c-myc,proliferation
                gastric cancer, foxc1, dkk1, c-myc, proliferation

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