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      Proteomic Approaches Identify Members of Cofilin Pathway Involved in Oral Tumorigenesis

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          Abstract

          The prediction of tumor behavior for patients with oral carcinomas remains a challenge for clinicians. The presence of lymph node metastasis is the most important prognostic factor but it is limited in predicting local relapse or survival. This highlights the need for identifying biomarkers that may effectively contribute to prediction of recurrence and tumor spread. In this study, we used one- and two-dimensional gel electrophoresis, mass spectrometry and immunodetection methods to analyze protein expression in oral squamous cell carcinomas. Using a refinement for classifying oral carcinomas in regard to prognosis, we analyzed small but lymph node metastasis-positive versus large, lymph node metastasis-negative tumors in order to contribute to the molecular characterization of subgroups with risk of dissemination. Specific protein patterns favoring metastasis were observed in the “more-aggressive” group defined by the present study. This group displayed upregulation of proteins involved in migration, adhesion, angiogenesis, cell cycle regulation, anti-apoptosis and epithelial to mesenchymal transition, whereas the “less-aggressive” group was engaged in keratinocyte differentiation, epidermis development, inflammation and immune response. Besides the identification of several proteins not yet described as deregulated in oral carcinomas, the present study demonstrated for the first time the role of cofilin-1 in modulating cell invasion in oral carcinomas.

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          Actin, a central player in cell shape and movement.

          The protein actin forms filaments that provide cells with mechanical support and driving forces for movement. Actin contributes to biological processes such as sensing environmental forces, internalizing membrane vesicles, moving over surfaces, and dividing the cell in two. These cellular activities are complex; they depend on interactions of actin monomers and filaments with numerous other proteins. Here, we present a summary of the key questions in the field and suggest how those questions might be answered. Understanding actin-based biological phenomena will depend on identifying the participating molecules and defining their molecular mechanisms. Comparisons of quantitative measurements of reactions in live cells with computer simulations of mathematical models will also help generate meaningful insights.
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            Role of tissue stroma in cancer cell invasion.

            Maintenance of epithelial tissues needs the stroma. When the epithelium changes, the stroma inevitably follows. In cancer, changes in the stroma drive invasion and metastasis, the hallmarks of malignancy. Stromal changes at the invasion front include the appearance of myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells. The main precursors of myofibroblasts are fibroblasts. The transdifferentiation of fibroblasts into myofibroblasts is modulated by cancer cell-derived cytokines, such as transforming growth factor-beta (TGF-beta). TGF-beta causes cancer progression through paracrine and autocrine effects. Paracrine effects of TGF-beta implicate stimulation of angiogenesis, escape from immunosurveillance and recruitment of myofibroblasts. Autocrine effects of TGF-beta in cancer cells with a functional TGF-beta receptor complex may be caused by a convergence between TGF-beta signalling and beta-catenin or activating Ras mutations. Experimental and clinical observations indicate that myofibroblasts produce pro-invasive signals. Such signals may also be implicated in cancer pain. N-Cadherin and its soluble form act as invasion-promoters. N-Cadherin is expressed in invasive cancer cells and in host cells such as myofibroblasts, neurons, smooth muscle cells, and endothelial cells. N-Cadherin-dependent heterotypic contacts may promote matrix invasion, perineural invasion, muscular invasion, and transendothelial migration; the extracellular, the juxtamembrane and the beta-catenin binding domain of N-cadherin are implicated in positive invasion signalling pathways. A better understanding of stromal contributions to cancer progression will likely increase our awareness of the importance of the combinatorial signals that support and promote growth, dedifferentiation, invasion, and ectopic survival and eventually result in the identification of new therapeutics targeting the stroma. Copyright 2003 John Wiley & Sons, Ltd.
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              Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia.

              Historically, the term 'keratin' stood for all of the proteins extracted from skin modifications, such as horns, claws and hooves. Subsequently, it was realized that this keratin is actually a mixture of keratins, keratin filament-associated proteins and other proteins, such as enzymes. Keratins were then defined as certain filament-forming proteins with specific physicochemical properties and extracted from the cornified layer of the epidermis, whereas those filament-forming proteins that were extracted from the living layers of the epidermis were grouped as 'prekeratins' or 'cytokeratins'. Currently, the term 'keratin' covers all intermediate filament-forming proteins with specific physicochemical properties and produced in any vertebrate epithelia. Similarly, the nomenclature of epithelia as cornified, keratinized or non-keratinized is based historically on the notion that only the epidermis of skin modifications such as horns, claws and hooves is cornified, that the non-modified epidermis is a keratinized stratified epithelium, and that all other stratified and non-stratified epithelia are non-keratinized epithelia. At this point in time, the concepts of keratins and of keratinized or cornified epithelia need clarification and revision concerning the structure and function of keratin and keratin filaments in various epithelia of different species, as well as of keratin genes and their modifications, in view of recent research, such as the sequencing of keratin proteins and their genes, cell culture, transfection of epithelial cells, immunohistochemistry and immunoblotting. Recently, new functions of keratins and keratin filaments in cell signaling and intracellular vesicle transport have been discovered. It is currently understood that all stratified epithelia are keratinized and that some of these keratinized stratified epithelia cornify by forming a Stratum corneum. The processes of keratinization and cornification in skin modifications are different especially with respect to the keratins that are produced. Future research in keratins will provide a better understanding of the processes of keratinization and cornification of stratified epithelia, including those of skin modifications, of the adaptability of epithelia in general, of skin diseases, and of the changes in structure and function of epithelia in the course of evolution. This review focuses on keratins and keratin filaments in mammalian tissue but keratins in the tissues of some other vertebrates are also considered.
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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
                5 December 2012
                : 7
                : 12
                : e50517
                Affiliations
                [1 ]Departamento de Biologia Molecular; Faculdade de Medicina (FAMERP), São José do Rio Preto, SP, Brazil
                [2 ]Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, Ribeirão Preto, SP, Brazil
                [3 ]Laboratório de Patologia, Hospital Heliópolis, São Paulo, SP, Brazil
                [4 ]Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais, Campinas, SP, Brazil
                [5 ]Departamento de Propedêutica e Clínica Integrada, Faculdade de Odontologia da Universidade Federal da Bahia, Salvador,BA, Brazil
                [6 ]Departamento de Estomatologia, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, SP, Brazil
                [7 ]Serviço de Cirurgia de Cabeça e Pescoço, Instituto do Câncer Arnaldo Vieira de Carvalho, São Paulo, SP, Brazil
                [8 ]Departamento de Patologia e Medicina Legal, Faculdade de Medicina (FAMERP), São José do Rio Preto, SP, Brazil
                [9 ]Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital Heliópolis, São Paulo, SP, Brazil
                [10 ]Divisão de Cirurgia de Cabeça e Pescoço, Departamento de Cirurgia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
                [11 ]Departamento de Produção Vegetal, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
                [12 ]Departamento de Epidemiologia, Faculdade de Saúde Pública da Universidade de São Paulo, São Paulo, SP, Brazil
                [13 ]Departamento de Genética e Biologia Evolutiva, Instituto de Biociências da Universidade de São Paulo, São Paulo, SP, Brazil
                Thomas Jefferson University, United States of America
                Author notes

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

                Conceived and designed the experiments: GMP AFP-L AMAS FDN AML EHT. Performed the experiments: GMP LMS AMCM FCAX DMG AV EEF JFG-F PMC OAC PM. Analyzed the data: GMP LMS AMCM AFP-L FCAX TH DMG AMAS VW-F FDN AML EHT. Contributed reagents/materials/analysis tools: AMCM AFP-L VW-F FDN AML EHT. Wrote the paper: GMP AFP-L FDN AML EHT. Revised the manuscript: GMP LMS AMCM AFP-L FCAX TH DMG AV EEF JFG-F PMC OAC PM AMAS VW-F FDN AML EHT. Approval of the final version of the manuscript: GMP LMS AMCM AFP-L FCAX TH DMG AV EEF JFG-F PMC OAC PM AMAS VW-F FDN AML EHT.

                Article
                PONE-D-12-22752
                10.1371/journal.pone.0050517
                3515627
                23227181
                f34cddc3-f149-40e9-80c5-0b3fb864752f
                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
                : 1 August 2012
                : 23 October 2012
                Page count
                Pages: 13
                Funding
                Funding was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo/FAPESP, Rede Proteoma do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/CAPES and Conselho Nacional de Pesquisas/CNPq, through financial support and fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Cancer Genetics
                Gene Function
                Gene Networks
                Proteomics
                Protein Abundance
                Spectrometric Identification of Proteins
                Medicine
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Oncology
                Basic Cancer Research
                Metastasis
                Cancers and Neoplasms
                Skin Tumors
                Oral Mucosal Cancers
                Oral Medicine
                Oral Diseases
                Otorhinolaryngology
                Head and Neck Cancers

                Uncategorized
                Uncategorized

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