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

Eva Serrano-Candelas, Erola Ainsua-Enrich, Arnau Navinés-Ferrer, Paulo Rodrigues, Alfonso García-Valverde, Sarah Bazzocco, Irati Macaya, Joaquín Arribas, César Serrano, Joan Sayós, Diego Arango, Margarita Martin

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. 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.
Original languageEnglish
Pages (from-to)1383-1397
JournalMolecular Oncology
Volume12
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • KIT
  • PDGFRA
  • SH3BP2
  • apoptosis
  • gastrointestinal stromal tumors

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