microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome

作者：Akcakaya P^*; Caramuta S; Ahlen J; Ghaderi M; Berglund E; Ostman A; Branstrom R; Larsson C; Lui W O

来源：British Journal of Cancer, 2014, 111(11): 2091-2102.

DOI：10.1038/bjc.2014.548

• microRNA
• PTPN18
• miR-125a-5p
• gastrointestinal stromal tumours
• imatinib
• resistance
• sarcoma
• prognosis

Background: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs.
Methods: The expression levels of microRNAs were quantified using microarray and RT-qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples.
Results: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival.
Conclusions: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST.

• 出版日期2014-11-25