RNA profiling and immunohistochemistry analyses of circRNAs in imatinib-resistant gastrointestinal stromal tumors.

BACKGROUND

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal sarcomas of the upper digestive tract. Imatinib is the first-line therapy for patients with metastatic or unresectable GISTs. However, the majority of GIST patients eventually develop imatinib resistance.

METHODS

To identify the factors that are responsible for imatinib resistance, we investigated the differentially expressed mRNAs and circRNAs in imatinib-naïve and imatinib-resistant GISTs via ceRNA microarrays. The expression levels of circ-BRIP1, circ-EPHB4 and their host genes were validated via quantitative real-time PCR analyses and formalin-fixed and paraffin-embedded (FFPE) tissue microarrays (TMAs).

RESULTS

We found that 107 mRNAs and 521 circRNAs were differentially expressed between imatinib-resistant and imatinib-naïve GIST tissue samples. Among them, circ-BRIP1, circ-EPHB4 and their host genes were upregulated in imatinib-resistant GISTs and associated with imatinib resistance, tumor relapse and progression, and metastasis in GIST patients. The expression level of EPHB4 was significantly greater in high-grade GISTs than in low-grade GISTs and was correlated with imatinib resistance.

CONCLUSIONS

Our results demonstrated that the circRNA in situ hybridization-immunohistochemistry could not only be applied to FFPE-TMAs for high-throughput analysis of circRNA expression in tumors but also suggested a possible role for circ-BRIP1, circ-EPHB4, and their host genes in the progression of GISTs.