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

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.

Molecular characterization and pathogenesis of gastrointestinal stromal tumor

“…and miR-107 is associated with imatinib resistance (136). By contrast, miR-218 increases the sensitivity of GIST cells to imatinib by inhibiting the PI3K/AKT pathway (137).…”

Signatures of circulating microRNA in four sarcoma subtypes

“…Downregulation of miR-320a correlates with shorter time to imatinib resistance in patients with GIST, indicating an important role in the mechanism underlying imatinib resistance in these patients [67]. Three other papers show that miRNAs, including miR-218, miR-125a-5p, and miR-518a-5p, play roles regulating sensitivity to imatinib [44,45,68].…”

miR‐4510 acts as a tumor suppressor in gastrointestinal stromal tumor by targeting APOC2

“…MicroRNAs (miRNAs) are small noncoding RNAs that contain 18–25 nucleotides, and regulate gene expression by binding to the 3′‐untranslated region (3′‐UTR) of targeted messenger RNAs (mRNAs; Akcakaya et al, 2014). miRNAs have been widely implicated in tumor progression, including proliferation, invasion, and metastasis.…”

“…miRNAs have been widely implicated in tumor progression, including proliferation, invasion, and metastasis. Recently, miRNAs have been demonstrated to be critical for the development and progression of GIST (Akcakaya et al, 2014; Long, Wu, Cai, Wang, & Zhou, 2018; Yun et al, 2018). For example, miR‐221 and miR‐222 are significantly downregulated in KIT‐positive GIST, and overexpression of these two miRNAs inhibits proliferation of GIST‐T1 cells by targeting KIT (Ihle et al, 2015).…”