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      Non-SMC Condensin I Complex Subunit H (NCAPH) Is Associated with Lymphangiogenesis and Drug Resistance in Oral Squamous Cell Carcinoma

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          Abstract

          Background: Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy. OSCC has strong invasive ability, and its malignant potential is closely associated with local expansion and lymph node metastasis. Furthermore, local or nodal recurrence worsens OSCC prognosis. In our previous cDNA microarray analysis, non-structural maintenance of chromosome (SMC) condensin I complex subunit H ( NCAPH) was identified as an upregulated gene in recurrent OSCC. Although NCAPH has several functions in tumors, its role in OSCC is unknown. Methods: In this study, we examined NCAPH expression in OSCC and performed a functional analysis of human OSCC cells. Results: NCAPH expression was higher in OSCC than in normal oral mucosa. In immunohistochemistry using 142 OSCC specimens, the immunostaining of NCAPH was strongly associated with nodal metastasis and lymphatic infiltration. In multivariate analysis using the Cox proportional hazards model, NCAPH expression was an independent poor prognostic indicator for OSCC. Moreover, NCAPH promoted the migration and adhesion of endothelial cells to OSCC cells and promoted the resistance to platinum anticancer drugs. Conclusions: Our present findings suggest that NCAPH is a novel diagnostic and therapeutic target in OSCC.

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          Most cited references25

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          The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012.

          By using data from the International Agency for Research on Cancer publication Cancer Incidence in 5 Continents and GLOBOCAN, this report provides the first consolidated global estimation of the subsite distribution of new cases of lip, oral cavity, and pharyngeal cancers by country, sex, and age for the year 2012. Major geographically based, sex-based, and age-based variations in the incidence of lip, oral cavity, and pharyngeal cancers by subsite were observed. Lip cancers were highly frequent in Australia (associated with solar radiation) and in central and eastern Europe (associated with tobacco smoking). Cancers of the oral cavity and hypopharynx were highly common in south-central Asia, especially in India (associated with smokeless tobacco, bidi, and betel-quid use). Rates of oropharyngeal cancers were elevated in northern America and Europe, notably in Hungary, Slovakia, Germany, and France and were associated with alcohol use, tobacco smoking, and human papillomavirus infection. Nasopharyngeal cancers were most common in northern Africa and eastern/southeast Asia, indicative of genetic susceptibility combined with Epstein-Barr virus infection and early life carcinogenic exposures (nitrosamines and salted foods). The global incidence of lip, oral cavity, and pharyngeal cancers of 529,500, corresponding to 3.8% of all cancer cases, is predicted to rise by 62% to 856,000 cases by 2035 because of changes in demographics. Given the rising incidence of lip, oral cavity, and pharyngeal cancers and the variations in incidence by subsites across world regions and countries, there is a need for local, tailored approaches to prevention, screening, and treatment interventions that will optimally reduce the lip, oral cavity, and pharyngeal cancer burden in future decades. CA Cancer J Clin 2017;67:51-64. © 2016 American Cancer Society.
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            Condensins: universal organizers of chromosomes with diverse functions.

            Condensins are multisubunit protein complexes that play a fundamental role in the structural and functional organization of chromosomes in the three domains of life. Most eukaryotic species have two different types of condensin complexes, known as condensins I and II, that fulfill nonoverlapping functions and are subjected to differential regulation during mitosis and meiosis. Recent studies revealed that the two complexes contribute to a wide variety of interphase chromosome functions, such as gene regulation, recombination, and repair. Also emerging are their cell type- and tissue-specific functions and relevance to human disease. Biochemical and structural analyses of eukaryotic and bacterial condensins steadily uncover the mechanisms of action of this class of highly sophisticated molecular machines. Future studies on condensins will not only enhance our understanding of chromosome architecture and dynamics, but also help address a previously underappreciated yet profound set of questions in chromosome biology.
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              Interaction of tumor cells and lymphatic vessels in cancer progression.

              Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive 'lymphovascular niche' for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.

                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                27 December 2019
                January 2020
                : 9
                : 1
                : 72
                Affiliations
                [1 ]Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; hiroz@ 123456naramed-u.ac.jp (H.S.); c-nakashima@ 123456naramed-u.ac.jp (C.N.); miyako@ 123456naramed-u.ac.jp (M.K.-S.); tkirita@ 123456naramed-u.ac.jp (T.K.)
                [2 ]Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara 634-8521, Japan
                Author notes
                [* ]Correspondence: sasa@ 123456naramed-u.ac.jp ; Tel.: +81-744-29-8849; Fax: +81-744-25-7308
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-1757-1275
                Article
                jcm-09-00072
                10.3390/jcm9010072
                7019401
                31892156
                0159b687-ceb4-410f-9edd-bcc7c407f6bc
                © 2019 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
                : 03 December 2019
                : 24 December 2019
                Categories
                Article

                ncaph,lymphangiogenesis,anticancer drug resistance,prognosis,oral cancer

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