Identification of critical microRNAs in gastrointestinal stromal tumor patients treated with Imatinib

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib mesylate was considered to be a breakthrough drug in clinical treatment of GIST, but GIST patients showed resistance against it. We aimed to identify critical microRNAs (miRNAs) related to imatinib resistance in imatinib-treated GIST patients. Microarray datasets under the accession number of GSE63159 and GSE45901 were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs (DEMs) that are related to imatinib resistance were identified. GO function and KEGG pathway enrichment analyses were performed, and lncRNA-miRNA-target gene regulatory networks were constructed. Finally, the critical miRNAs and their target genes that are related to imatinib resistance or sensitivity were identified. In total, 20 DEMs in the GSE63159 dataset (7 significantly up-regulated and 13 down-regulated) and 23 DEMs in the GSE45901 dataset (8 up-regulated and 15 down-regulated) were identified. In lncRNA-miRNA-target gene regulatory networks, five critical miRNAs and 109 target genes were identified. GO function and KEGG pathway enrichment analysis showed that the target genes of DEMs were mainly involved in several signaling pathways, such as focal adhesion and the GnRH signaling pathway. Among the five miRNAs, the overexpression of hsa-miR-28-5p and hsa-miR-125a-5p had significant correlation to imatinib resistance or imatinib sensitivity in GIST patients. Hsa-miR-28-5p and hsa-miR-125a-5p may be involved in the development and progression of GIST, and they may be able to serve as prognostic markers for imatinib-response in GIST patients.

Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor

“…Also, the integrin-mediated signaling transduction pathway of focal adhesion kinase (FAK) was identified by the Gene Expression Omnibus (GEO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis as the pathway where the significantly different ncRNAs between the imatinib treated GIST patients with and without resistance were enrich in ( Zhang et al, 2018 ). Moreover, FAK is verified as the downstream pathway of PTPN18 contributing to the imatinib resistance in GISTs, which is regulated by miRNA-125a-5p ( Akcakaya et al, 2014 ; Huang et al, 2018 ).…”

MicroRNAs as Predictive Biomarkers of Resistance to Targeted Therapies in Gastrointestinal Tumors

“…Being overexpressed in imatinib-resistant GIST samples and displaying a significant correlation to imatinib response, miR-28-5p has been proven to function as an oncomiR. However, very little is known about this miRNA and therefore further research is required to confirm these findings [87].…”

Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors

“…Zhang et al performed in silico analyses using GO function and KEGG pathway enrichment as well as the lncRNA-miRNA-target gene regulatory network built of the microarray datasets deposited by Akçakaya et al [110]. These studies highlighted miR-28-5p and-not surprisingly-miR-125a-5p, both of which displayed a significant correlation to imatinib resistance and imatinib sensitivity [117]. Additionally, Shi et al uncovered a series of up-or downregulated miRNAs by comparing imatinib-naïve with imatinib-resistant GIST samples [118].…”

“…These prognostic biomarkers may be further developed into a more quantitative risk evaluation for GIST which is now based on the mitotic index, tumor size and tumor location. Finally, miRNAs associated with imatinib resistance [30,110,114,115,[117][118][119] may be used to signal evolving imatinib resistance enabling early clinical intervention. Interestingly, lncRNAs have also been identified that could be used for diagnostic purposes [129,131,133] or are specifically linked to high-risk/advanced GIST [108,122,123,125,128] and imatinib resistance [126,127,130].…”