Open AccessSilencing of adaptor protein SH 3 BP 2 reduces KIT / PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth
Author(s) -
SerranoCandelas Eva,
AinsuaEnrich Erola,
NavinésFerrer Arnau,
Rodrigues Paulo,
GarcíaValverde Alfonso,
Bazzocco Sarah,
Macaya Irati,
Arribas Joaquín,
Serrano César,
Sayós Joan,
Arango Diego,
Martin Margarita
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12332
Subject(s) - microphthalmia associated transcription factor , cancer research , pdgfra , imatinib mesylate , gene silencing , proto oncogene proteins c kit , biology , imatinib , stromal cell , gist , chemistry , microbiology and biotechnology , stem cell factor , stem cell , progenitor cell , transcription factor , myeloid leukemia , biochemistry , gene
Gastrointestinal stromal tumors ( GIST s) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GIST s 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 SH 3 Binding Protein 2 ( SH 3 BP 2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH 3 BP 2 is expressed in primary tumors and cell lines from GIST patients and that SH 3 BP 2 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 GIST s. Interestingly, MITF is reduced after SH 3 BP 2 silencing. Importantly, reconstitution of both SH 3 BP 2 and MITF restores cell viability. Furthermore, SH 3 BP 2 silencing significantly reduces cell migration and tumor growth of imatinib‐sensitive and imatinib‐resistant cells in vivo . Altogether, SH 3 BP 2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in imatinib‐sensitive and imatinib‐resistant GIST s.