microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome |
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Authors: | P Ak?akaya S Caramuta J ?hlen M Ghaderi E Berglund A ?stman R Br?nstr?m C Larsson W-O Lui |
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Institution: | 1.Department of Oncology–Pathology, Karolinska Institutet, Stockholm, Sweden;2.Cancer Center Karolinska, Karolinska University Hospital, Stockholm SE-17176, Sweden;3.Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;4.Department of Breast and Endocrine Surgery, Endocrine and Sarcoma Surgery Unit, Karolinska University Hospital, Stockholm SE-17176, Sweden |
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Abstract: | 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. |
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Keywords: | microRNA PTPN18 miR-125a-5p gastrointestinal stromal tumours imatinib resistance sarcoma prognosis |
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