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      Progression of Oral Squamous Cell Carcinoma Accompanied with Reduced E-Cadherin Expression but Not Cadherin Switch

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          Abstract

          The cadherin switch from E-cadherin to N-cadherin is considered as a hallmark of the epithelial-mesenchymal transition and progression of carcinomas. Although it enhances aggressive behaviors of adenocarcinoma cells, the significance and role of cadherin switch in squamous cell carcinomas (SCCs) are largely controversial. In the present study, we immunohistochemically examined expression of E-cadherin and N-cadherin in oral SCCs ( n = 63) and its implications for the disease progression. The E-cadherin-positive carcinoma cells were rapidly decreased at the invasive front. The percentage of carcinoma cells stained E-cadherin at the cell membrane was reduced in parallel with tumor dedifferentiation ( P<0.01) and enhanced invasion ( P<0.01). In contrast, N-cadherin-positive cells were very limited and did not correlate with the clinicopathological parameters. Mouse tongue tumors xenotransplantated oral SCC cell lines expressing both cadherins in vitro reproduced the reduction of E-cadherin-positive carcinoma cells at the invasive front and the negligible expression of N-cadherin. These results demonstrate that the reduction of E-cadherin-mediated carcinoma cell-cell adhesion at the invasive front, but not the cadherin switch, is an important determinant for oral SCC progression, and suggest that the environments surrounding carcinoma cells largely affect the cadherin expression.

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          Most cited references35

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Cadherin switching.

            The cadherin molecules at adherens junctions have multiple isoforms. Cadherin isoform switching (cadherin switching) occurs during normal developmental processes to allow cell types to segregate from one another. Tumor cells often recapitulate this activity and the result is an aggressive tumor cell that gains the ability to leave the site of the tumor and metastasize. At present, we understand some of the mechanisms that promote cadherin switching and some of the pathways downstream of this process that influence cell behavior. Specific cadherin family members influence growth-factor-receptor signaling and Rho GTPases to promote cell motility and invasion. In addition, p120-catenin probably plays multiple roles in cadherin switching, regulating Rho GTPases and stabilizing cadherins.
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              Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex.

              In epithelial cells, tyrosine kinases induce the tyrosine phosphorylation and ubiquitination of the E-cadherin complex, which induces endocytosis of E-cadherin. With a modified yeast 2-hybrid system, we isolated Hakai, an E-cadherin binding protein, which we have identified as an E3 ubiquitin-ligase. Hakai contains SH2, RING, zinc-finger and proline-rich domains, and interacts with E-cadherin in a tyrosine phosphorylation-dependent manner, inducing ubiquitination of the E-cadherin complex. Expression of Hakai in epithelial cells disrupts cell--cell contacts and enhances endocytosis of E-cadherin and cell motility. Through dynamic recycling of E-cadherin, Hakai can thus modulate cell adhesion, and could participate in the regulation of epithelial--mesenchymal transitions in development or metastasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                23 October 2012
                : 7
                : 10
                : e47899
                Affiliations
                [1 ]Department of Biochemistry, The Nippon Dental University, Tokyo, Japan
                [2 ]Department of Pathology, The Nippon Dental University, Tokyo, Japan
                [3 ]Research Center for Odontology, The Nippon Dental University, Tokyo, Japan
                [4 ]Department of Oral Surgery, Kanazawa University, Kanazawa, Japan
                Okayama University, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KI. Performed the experiments: TH YS GM YT MN. Analyzed the data: TA KI. Contributed reagents/materials/analysis tools: SK. Wrote the paper: KI.

                Article
                PONE-D-12-12191
                10.1371/journal.pone.0047899
                3479144
                23110125
                cd40a107-98f9-42d3-ac35-4f7be97703fc
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 April 2012
                : 18 September 2012
                Page count
                Pages: 8
                Funding
                This study was supported by a grant from the Japan Society for the Promotion of Science #22592103. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Oncology
                Basic Cancer Research
                Tumor Physiology
                Cancers and Neoplasms
                Head and Neck Tumors
                Head and Neck Squamous Cell Carcinoma
                Oral Medicine
                Oral Diseases

                Uncategorized
                Uncategorized

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