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Network-based genetic profiling, and therapeutic target identification of Thyroid Cancer

Ali Hossain,T. Asa,Julian M. W. Quinn,Mijanur Rahman,F. Huq,M. A. Moni

Published 2018 in bioRxiv

ABSTRACT

Molecular mechanisms that underlie the pathogenesis and progression of malignant thyroid cancer (TC) are poorly understood. In this study, we employed network-based integrative analyses of TC lesions to identify key molecules that are possible hub genes and proteins in molecular pathways active in TC. We thus studied a microarray gene expression dataset (GSE82208, n=52) that compared TC to benign thyroid tumours (follicular thyroid adenomas) in order to identify differentially expressed genes (DEGs) in TC. We used Gene Ontology (GO) and KEGG pathway analyses to identify potential gene and pathways roles as well as candidate hub genes identified by protein-protein interaction (PPI) analysis. TC showed altered levels of 598 gene transcripts, with 133 genes upand 465 genes down-regulated. We observed four significant pathways (One carbon pool by folate, p53 signaling, Progesterone-mediated oocyte maturation signaling and Cell cycle pathways) connected with the significantly up-regulated DEGs; eight pathways were connected with the significantly down-regulated DEGs in TC. We observed ten significant GO groups connected with the significantly up-regulated DEGs and eighty connected with the significantly down-regulated DEGs in TC. The PPI analysis identified 12 potential hub genes based on degree and betweenness centrality. These included TOP2A, JUN, EGFR, CDK1, FOS, CDKN3, EZH2, TYMS, PBK, CDH1, UBE2C and CCNB2. Moreover, transcription factors (TFs) that may influence the observed TC gene expression were identified, including FOXC1, GATA2, YY1, FOXL1, E2F1, NFIC, SRF, TFAP2A, HINFP, and CREB1. We also identified potential microRNA (miRNAs) that may also affect transcript levels of DEGs, including hsa-mir-335-5p, -26b-5p, -124-3p, -16-5p, -1925p, -1-3p, -17-5p, -92a-3p, -215-5p, and -20a-5p. Thus, our study identified DEGs, molecular pathways, TFs and miRNAs that identify pathways and molecular mechanisms that may underly malignant progression in TC. These include novel candidates for further studies to identify new TC biomarkers and therapeutic targets.

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