Gyvyte Ugne, Juzenas Simonas, Salteniene Violeta, Kupcinskas Juozas, Poskiene Lina, Kucinskas Laimutis, Jarmalaite Sonata, Stuopelyte Kristina, Steponaitiene Ruta, Hemmrich-Stanisak Georg, Hübenthal Matthias, Link Alexander, Franke Sabine, Franke Andre, Pangonyte Dalia, Lesauskaite Vaiva, Kupcinskas Limas, Skieceviciene Jurgita
Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Oncotarget. 2017 Jun 6;8(23):37225-37238. doi: 10.18632/oncotarget.16664.
Deregulation of miRNAs has been observed virtually in all major types of cancer, whereas the miRNA signature in GIST is not well characterized yet. In this study the first high-throughput miRNA profiling of 15 paired GIST and adjacent normal tissue samples was performed using small RNA-seq approach and differentially expressed miRNAs as well as isomiRNAs were defined. Highly significantly deregulated miRNAs were selected for validation by Taq-Man low-density array in replication group of 40 paired samples. Validated miRNAs were further subjected to enrichment analysis, which revealed significantly enriched KEGG pathways in the main GIST associated pathways. Further, we used an integrated analysis of miRNA-mRNA correlations for KIT and PDGFRA target genes and found a significant correlation between all of the enriched miRNAs and their target gene KIT. Results of the phenotype analysis showed miR-509-3p to be up-regulated in epithelioid and mixed cell types compared to spindle type, whereas miR-215-5p showed negative correlation with risk grade of GIST. These data reveal a detailed miRNA profile of GIST and highlight new candidates that may be important in the development of malignant disease.
事实上，在所有主要类型的癌症中都观察到了微小RNA（miRNA）的失调，而胃肠道间质瘤（GIST）中的miRNA特征尚未得到充分表征。在本研究中，使用小RNA测序方法对15对GIST及其相邻正常组织样本进行了首次高通量miRNA谱分析，并确定了差异表达的miRNA以及异源miRNA。选择高度显著失调的miRNA，通过Taq-Man低密度阵列在40对样本的复制组中进行验证。对经过验证的miRNA进一步进行富集分析，结果显示在主要的GIST相关通路中KEGG通路显著富集。此外，我们对KIT和PDGFRA靶基因进行了miRNA- mRNA相关性的综合分析，发现所有富集的miRNA与其靶基因KIT之间存在显著相关性。表型分析结果显示，与梭形细胞类型相比，miR-509-3p在上皮样和混合细胞类型中上调，而miR-215-5p与GIST的风险分级呈负相关。这些数据揭示了GIST详细的miRNA谱，并突出了可能在恶性疾病发展中起重要作用的新候选分子。
