MICROARRAY TECHNOLOGY REVEALS POTENTIALLY NOVEL GENES AND PATHWAYS INVOLVED IN NON-FUNCTIONING PITUITARY ADENOMAS
Qiao X, Wang H, Wang X, Zhao B, Liu J,
*Corresponding Author: Jun Liu, M.D., Department of Neurosurgery, The Second Hospital of Jilin University, 218 Ziqiang Road, Changchun, 130021, Jilin Province, People’s Republic of China. Tel: +86-138-0431-7080. E-mail: LiuJun66@126.com
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RESULTS

Differentially Expressed Genes and Clusters. A total of 604 DEGs were acquired between NFPAs and controls, involving 177 up- and 427 down-regulated genes. The top 10 up-regulated genes and top 10 down-regulated genes are shown in Table 1. The 604 DEGs and 23 samples were clustered, and DEGs could well differentiate the disease samples from the healthy controls (Figure 1). Functions and Pathways. The GO enrichment analysis and KEGG pathway analysis were performed to reveal the key biological functions altered in NFPAs. As shown in Table 2, 12 pathways were significantly enriched, which were mainly associated with signaling pathway and receptor interaction. In GO enrichment analysis, DEGs were significantly enriched in 1037 biological process terms mainly about cell communication and signaling, 65 cellular component terms mainly related with an extracellular matrix (ECM), plasma membrane, and collagen, as well as 186 molecular function terms mainly associated with transcription factor activity and receptor binding (Table 2). In order to better understand the positions of DEGs in pathways and their roles in the development of NFPAs, we visualized four significant pathways that had been reported to participate in the pathogenesis of NFPAs or PAs, including MAPK signaling pathway [10] (Figure 2), p53 signaling pathway [24] (Figure 3), transforming growth factor β (TGFβ), signaling pathway [25] (Figure 4), and Jak-STAT signaling pathway [8] (Figure 5). Protein-Protein Interaction Network of Differentially Expressed Genes. For the 604 DEGs, the PPI network was constructed using information from STRING v10 (Figure 6). The whole network consisted of 115 upregulated DEGs, 305 down-regulated DEGs and 1379 PPIs (Figure 6). Potential Novel Non-Functioning Pituitary Adenoma- Related Genes and Sub-Network. Known disease genes were obtained from the CTD database (http://ctdbase.org/) and compared with the DEGs in the PPI network. Consequently, 99 up- and 288 down-regulated DEGs were known disease genes, e.g. EGFR (epidermal growth factor receptor, degree = 63) [10,26-28] and ESR1 (estrogen receptor 1, degree = 48) [29] (Figure 6). In contrast, 16 up- and 17 down-regulated DEGs were potential novel NFPA-related genes, e.g. COL4A5 (collagen type IV α5, degree = 17), LHX3 (LIM homeobox protein 3, degree = 11), MSN (moesin, degree = 11) and GHSR (growth hormone secretagogue receptor, degree = 10) (Figure 6). Moreover, COL4A5 interacted with known NFPA-related genes such as EGFR, LHX3 interacted with known NFPAsrelated genes like PRL (Prolactin), and MSN interacted with known NFPA-related genes such as EGFR. Among the top 10 up-regulated genes and top 10 down-regulated genes, only 12 DEGs interacted with other DEGs [e.g. CDKN2A (cyclin-dependent kinase inhibitor 2A)-IDH1 (isocitrate dehydrogenase 1)], and all 12 DEGs were known disease genes [e.g. DLK1 (δ-like 1 homologue)] (Figure 7). In addition, potential NFPA-related gene GHSR interacted with the top DEG GH1 (growth hormone 1).



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