Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth. Issue 8 (30th June 2018)

• Record Type: Journal Article
• Authors: Serrano‐Candelas, Eva; Ainsua‐Enrich, Erola; Navinés‐Ferrer, Arnau; Rodrigues, Paulo; García‐Valverde, Alfonso; Bazzocco, Sarah; Macaya, Irati; Arribas, Joaquín; Serrano, César; Sayós, Joan; Arango, Diego; Martin, Margarita
• Is Part Of: Molecular oncology. Volume 12:Issue 8(2018)
• Page Start: 1383
• Page End: 1397
• Publication Date: 2018-06-30
• Subjects: apoptosis -- gastrointestinal stromal tumors -- KIT -- PDGFRA -- SH3BP2; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12332
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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 (SH3BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 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 SH3BP2 silencing. Importantly, reconstitution of both SH3BP2 and MITF restores cell viability. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of imatinib‐sensitive and imatinib‐resistant cells in vivo . Altogether, SH3BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in imatinib‐sensitive and imatinib‐resistant GISTs. Abstract : Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Complete responses to the current treatments are rare, and most patients develop resistance to these drugs over time. Our data show that silencing of SH3BP2, a novel molecule, reduces survival in drug‐resistant oncogenic cell lines. Thus, SH3BP2 or partners may be potential targets for GIST treatment.