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      Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth

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          Gastrointestinal stromal tumors ( GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 ( SH3 BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3 BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3 BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in imatinib‐sensitive and imatinib‐resistant GIST cells. The microphthalmia‐associated transcription factor ( MITF), involved in KIT expression in mast cells and melanocytes, is expressed in GISTs. Interestingly, MITF is reduced after SH3 BP2 silencing. Importantly, reconstitution of both SH3 BP2 and MITF restores cell viability. Furthermore, SH3 BP2 silencing significantly reduces cell migration and tumor growth of imatinib‐sensitive and imatinib‐resistant cells in vivo. Altogether, SH3 BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in imatinib‐sensitive and imatinib‐resistant GISTs.

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          Most cited references 52

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          Diagnosis of gastrointestinal stromal tumors: A consensus approach.

          As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GISTs), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and the development of novel and effective therapy for GISTs using the receptor tyrosine kinase inhibitor STI-571, these tumors have become the focus of considerable attention by pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a source of confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time. Copyright 2002, Elsevier Science (USA). All rights reserved.
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            PDGFRA activating mutations in gastrointestinal stromal tumors.

            Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
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              Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.

              Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.

                Author and article information

                Mol Oncol
                Mol Oncol
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                30 June 2018
                August 2018
                : 12
                : 8 ( doiID: 10.1002/mol2.2018.12.issue-8 )
                : 1383-1397
                [ 1 ] Biochemistry Unit, Biomedicine Department Faculty of Medicine University of Barcelona Spain
                [ 2 ] Laboratory of Clinic and Experimental Immunoallergy IDIBAPS Barcelona Spain
                [ 3 ] Group of Biomedical Research in Digestive Tract Tumors CIBBIM‐Nanomedicine Vall d'Hebron University Hospital Research Institute (VHIR) Autonomous University of Barcelona Spain
                [ 4 ] Preclinical Research Program Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain
                [ 5 ] The Catalan Institute of Research and Advanced Studies (ICREA) Barcelona Spain
                [ 6 ] CIBERONC Barcelona Spain
                [ 7 ] Department of Biochemistry and Molecular Biology Universitat Autónoma de Barcelona Bellaterra Spain
                [ 8 ] Vall d'Hebron University Hospital Barcelona Spain
                [ 9 ] Immune Regulation and Immunotherapy Group CIBBIM‐Nanomedicine Vall d'Hebron University Hospital Research Institute (VHIR) Autonomous University of Barcelona Spain
                Author notes
                [* ] Correspondence

                M. Martin, Biochemistry Unit, Biomedicine Department, Faculty of Medicine, University of Barcelona, Carrer de Casanova 143, E‐08036 Barcelona, Spain

                Fax: +34 93 4035882

                Tel: +34 93 4024541

                E‐mail: martin_andorra@

                © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 0, Pages: 15, Words: 8037
                Funded by: Instituto de Salud Carlos III
                Award ID: PI12/03103
                Award ID: PI12/01095
                Award ID: PI16/00540
                Award ID: AC15/00066
                Award ID: PI16/01371
                Funded by: Secretaría de Estado de Investigación, Desarrollo e Innovación
                Award ID: SAF2015‐68124‐R
                Research Article
                Research Articles
                Custom metadata
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:01.08.2018

                Oncology & Radiotherapy

                apoptosis, gastrointestinal stromal tumors, kit, pdgfra, sh3bp2


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