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      Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target

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          Abstract

          CEMIP (KIAA1199) was identified as migratory indicator protein which had been crudely studied in the last decade. Firstly its mutation site was reported to cause hearing loss due to the folding change of protein structure, meanwhile the over-expression of CEMIP referred to dreadful invasion and uncontrolled proliferation of tumor with distant metastasis, dedifferentiation, and limited survival opportunity of patients. Especially, over-expressed CEMIP also protected malignant tumor from strict microenvironment in hypoxia, low glucose and cracked barrier, leading to enhanced adaptability of tumor by stimulating the Wnt, EGFR, FGFR pathway. Here, we intend to elaborate the clinical function and dysregulation of CEMIP under the tumorous circumstance since CEMIP plays an important role in cytokine pathway and its over-expression in tumors provide a novel target for individual therapy. Targeting CEMIP would thereby dysregulate the cytokine pathway which would in turn, decide the growth and death of the vicious tumour cells.

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          Most cited references49

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          Transcriptome profile of human colorectal adenomas.

          Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the beta-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.
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            EGFR and NF-κB: partners in cancer.

            Oncogenic proteins cooperate to promote tumor development and progression by sustaining cell proliferation, survival and invasiveness. Constitutive epidermal growth factor receptor (EGFR) and nuclear factor κb (NF-κB) activities are seen in multiple solid tumors and combine to provide oncogenic signals to cancer cells. Understanding how these oncogenic pathways are connected is crucial, given their role in intrinsic or acquired resistance to targeted anticancer therapies. We review molecular mechanisms by which both EGFR- and NF-κB-dependent pathways establish positive loops to increase their oncogenic potential. We also describe how NF-κB promotes resistance to EGFR inhibitors.
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              KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.

              Hyaluronan (HA) has an extraordinarily high turnover in physiological tissues, and HA degradation is accelerated in inflammatory and neoplastic diseases. CD44 (a cell surface receptor) and two hyaluronidases (HYAL1 and HYAL2) are thought to be responsible for HA binding and degradation; however, the role of these molecules in HA catabolism remains controversial. Here we show that KIAA1199, a deafness gene of unknown function, plays a central role in HA binding and depolymerization that is independent of CD44 and HYAL enzymes. The specific binding of KIAA1199 to HA was demonstrated in glycosaminoglycan-binding assays. We found that knockdown of KIAA1199 abolished HA degradation by human skin fibroblasts and that transfection of KIAA1199 cDNA into cells conferred the ability to catabolize HA in an endo-β-N-acetylglucosaminidase-dependent manner via the clathrin-coated pit pathway. Enhanced degradation of HA in synovial fibroblasts from patients with osteoarthritis or rheumatoid arthritis was correlated with increased levels of KIAA1199 expression and was abrogated by knockdown of KIAA1199. The level of KIAA1199 expression in uninflamed synovium was less than in osteoarthritic or rheumatoid synovium. These data suggest that KIAA1199 is a unique hyaladherin with a key role in HA catabolism in the dermis of the skin and arthritic synovium.
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2017
                20 July 2017
                : 8
                : 12
                : 2238-2246
                Affiliations
                [1 ]Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
                [2 ]Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
                [3 ]Quality Assurance Department, Bristol Laboratories Limited, 5 Traynor Way, Whitehouse Business Park, Peterlee, County Durham, SR8 2RU, United Kingdom
                [4 ]Department of Pharmacy, Guangxi Bone Hospital, Nanning, 530000, Guangxi Zhuang Autonomous Region, People's Republic of China
                [5 ]Department of Research, Nanning Children Rehabilitation Center, Nanning, 530003, Guangxi Zhuang Autonomous Region, People's Republic of China
                Author notes
                ✉ Corresponding authors: Li Li, Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region, No.6 Taoyuan Road, Nanning 530021, Guangxi Zhuang Autonomous Region, People's Republic of China; Tel: +86-771-2186160; E-mail: snailwlily@ 123456163.com (Li L); And Dr. Lin-Hai Yan, Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, No. 71, Hedi Road, Nanning 530021, Guangxi Zhuang Autonomous Region, People's Republic of China. Tel: +86-771-5344230; E-mail: lhyan@ 123456gxmu.edu.cn (Yan LH).

                Competing Interests: None declared.

                Article
                jcav08p2238
                10.7150/jca.19295
                5560141
                28819426
                a23b35e0-7819-46ea-8395-a97f57a0e0ba
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 22 January 2017
                : 25 April 2017
                Categories
                Review

                Oncology & Radiotherapy
                cemip/kiaa1199,cancer,cytokine signaling pathway,hyaluronic acid.
                Oncology & Radiotherapy
                cemip/kiaa1199, cancer, cytokine signaling pathway, hyaluronic acid.

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