Pathology, research and practice 2017 09 27213(11) 1344-1354 pii 10.1016/j.prp.2017.09.024
This research aims to investigate the prospective molecular mechanism of miR-375 in Medullary Thyroid Cancer (MTC).
MATERIAL AND METHODS
The expression level of miR-375 in MTC was explored with microarray data from Gene Expression Omnibus (GEO). To gather the putative target genes of miR-375, we selected eligible datasets in GEO, in which antagomir-375 and premir-375 were transfected to provide the miR-375-related genes. Subsequently, we attained the intersection of the results of GEO microarray data and 12 online target genes prediction database as the prospective target genes. Furthermore, we conducted in silico analysis including gene ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways annotations and Protein-Protein Interactions (PPI) analysis to provide an overview of the function of miR-375 in MTC. Finally, data from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (THPA) were used for a validation.
Up-regulation could be confirmed with the data from GSE40807. GEO dataset GSE67742 provided 10,596 miR-375-related genes, while 12 online prediction databases showed that 3352 target genes appeared no less than four times. Finally, the intersection of the two groups of genes included 1132 prospective targets. In aspect of functional annotation, negative regulation of transcription from RNA polymerase II promoter (P=9.83E-06), golgi membrane (P=9.98E-05) and pathway of protein binding (P=3.63E-07) were highlighted as the most enriched terms with GO analysis. With regards to PPI network, 162 hub genes that interacted with no less than 10 other different genes was visualized, among which PI3K/Akt signaling pathway was the most enriched pathway as assessed by KEGG. Furthermore, two genes (JAK2 and NGFR) in PI3K/Akt signaling pathway showed down-regulated patterns in both mRNA and protein levels.
The higher expression level of miR-375 might play a pivotal role in the tumorigenesis of MTC via targeting multiple key pathways, especially PI3K/Akt pathway. However, the exact molecular mechanism of miR-375 needs to be verified with in-depth investigation in the future.