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
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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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