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
page: 5

DISCUSSION

Non-functioning pituitary adenomas comprise about 34.0% of pituitary tumors, while their molecular mechanism is still incompletely understood [5]. In the current study, we comprehensively analyzed the gene expression profile of NFPAs and healthy pituitary glands. As a result, 604 DEGs were identified between NFPAs and controls, including 177 up- and 427 down-regulated genes, which were much less than those identified by Michaelis et al. [14]. However, in the current study, we analyzed the same microarray data using different software, algorithms, and analysis criteria (corrected p value <0.05 and [log2 FC] >2) in order to focus on the DEGs that were more significant. In the current study, mean FC of the up-regulated genes was 6.6, and mean FC of the down-regulated genes was –19.2, which were different from those in the previous study by Michaelis et al. [14] (4.5 and –32.2, respectively). The differences of mean FC values might be caused by the different DEG sets in the two studies [14]. The major DEGs found by Michaelis et al. [14] had similar expression change patterns in the current study, e.g. for the PLAGL1, CDKN1A, RPRM, PMAIP1, MDM2, GADD45A, GADD45B and GADD45G genes. Of the top DEGs, DLK1, GH1, CDKN2A and MEG3 were significantly down-regulated in NFPAs in comparison with normal pituitary glands in this study. According to the report, the MEG3 and DLK1-MEG3 locus are silenced in human NFPAs of gonadotroph origin, and DLK1-MEG3 locus plays a tumor suppressor role in NFPAs [30]. Based on proteome data and microarray data or reverse transcription quantitative real-time polymerase chain reaction analysis, Moreno et al. [31] found that DLK1, GH1 and PRL are down-regulated in NFPAs when compared with normal pituitary glands, whereas IDH1 is significantly up-regulated. The CDKN2A and DLK1 are considered as biomarkers of gonadotroph tumors by Cai et al. [15], and gene silencing mediated by hypermethylation of the CpG island within exon 1 in CDKN2A is associated with NFPAs [32]. As clearly shown in Figure 7, the expression change patterns of known disease genes DLK1, GH1, PRL, CDKN2A and IDH1, were consistent with the aforementioned studies [30-32], demonstrating the high accuracy of our results. Expressions of EGFR in NFPAs varied in different studies [10,26-28]. In the current study, EGFR showed low expression in NFPAs (Figure 7), and it interacted with known disease gene CDKN2A, indicating that low expression of EGFR might be associated with NFPAs. We also found that CDKN2A was a top DEG, and it interacted with 22 DEGs in the whole PPI network and most DEGs in the PPI sub-network, suggesting that CDKN2A might play a crucial role in the progression of NFPAs. Furthermore, potential novel genes were identified (Figure 6), especially COL4A5, LHX3, MSN and GHSR. The role of these genes in NFPAs has not been investigated by previous studies. According to the report, mRNA level of GHSR in NFPAs is lower than that in growth hormoneproducing PAs [33]. In the present study, COL4A5, LHX3, MSN and GHSR were significantly down-regulated in NFPAs in comparison with normal controls, and they interacted with known NFPA-related genes such as EGFR, PRL, and GH1. These results indicated that COL4A5, LHX3, MSN and GHSR might participate in the initiation and progression of NFPAs via interaction with EGFR, PRL and GH1, respectively. We found DEGs were significantly enriched in the p53 (Figure 3) and Jak-STAT signaling pathways (Figure 5), which had been reported to take part in PAs pathogenesis [8,24]. The p53 signaling pathway is involved in biological processes such as cell cycle arrest, apoptosis, senescence, DNA repair and changes in metabolism. Expression level of p53 correlates with the proliferative state of PAs [24]. The Jak-STAT pathway is an important downstream pathway for growth factor receptors and cytokine receptors, and it is involved in the regulation of cell proliferation and survival [34,35]. As all of the DEGs mapped on these pathways were remarkably down-regulated in NFPAs, p53 and Jak-STAT signaling pathways might play roles in the progression of NFPAs. In addition, DEGs were significantly enriched in GO terms mainly about cell communication, signaling, ECM, plasma membrane, collagen, transcription factor activity and receptor binding (Table 2). The ECM, plasma membrane, and receptor binding are the basis of cell communication and signaling between pituitary cells, which play crucial roles in the development and invasion of PAs [36, 37]. As DEGs mapped on these GO terms were remarkably dysregulated in NFPAs, cell communication and signaling might contribute to the progression of NFPAs. In conclusion, a number of genes (e.g. COL4A5, LHX3, MSN and GHSR) identified in this study, might be potential novel NFPA-related genes. Furthermore, cell communication and signaling pathways (e.g. p53 and Jak- STAT) might be implicated in the pathogenesis of NFPAs. Currently, no effective medical therapies are available for NFPAs, due to their unclear mechanism. Although further validation is required, our findings might provide information to guide future researchers and even benefit the development of medical therapy for NFPAs. Declaration of Interest. This study was supported by Natural Science Fund (grant number: 20150101193JC). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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