Abstract
ABSTRACTThe involvement of long non-coding RNAs (lncRNAs) during tumorigenesis is a recent emerging theme. Yet no systematic evaluation of lncRNAs has been previously reported for non-functioning pituitary adenoma (NFPA), a fairly common type of intracranial tumor. Here, we report the first genome-wide expression profile for lncRNAs and mRNAs in NFPA, using formalin-fixed and paraffin-embedded tissue specimens. Using microarray analyses, we identified 113 lncRNAs and 80 mRNAs differentially expressed in NFPA; this list includes lncRNAs previously implicated in a variety of cancers. Using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) we further confirmed differential expression in NFPA for ten of the 113 lncRNAs. Using these ten doubly confirmed lncRNAs, we constructed an lncRNA-mRNA co-expression network comprising of 130 specific lncRNA-mRNA co-expression relationships. In addition, we conducted GO and KEGG analyses for the 80 mRNAs differentially expressed in NFPA. Our microarray and qRT-PCR analyses provided a working list of lncRNAs that may be functionally relevant to NFPA tumorigenesis. Our co-expression network in turn connected these largely uncharacterized lncRNAs to specific mRNAs, whose roles we further elucidated via GO and KEGG analyses, thus providing specific, testable hypotheses for the functions of these lncRNAs. Together, our study laid the foundation for future investigation of the specific function and mechanism by which lncRNAs are involved in NFPA tumorigenesis.
Highlights
Pituitary adenomas (PAs) account for approximately 15% of intracranial primary tumors with a prevalence of close to one case per 1000 individuals (Daly et al, 2006; Fernandez et al, 2010)
For each lncRNAmRNA pair (800 total pairs examined), we evaluated whether the expression levels of the long non-coding RNAs (lncRNAs) and the mRNA are consistently linearly correlated across all ten nonfunctioning pituitary adenoma (NFPA) or normal pituitary (NP) samples by calculating the Pearson Correlation Coefficient (PCC, Prieto et al, 2008), which has been widely used to measure linear correlation co-expression (Li et al, 2013; Gu et al, 2015; Wang et al, 2015)
We focused on ten specific lncRNAs (Fig. 3) when we constructed this co-expression network, because these lncRNAs have been validated to be differentially expressed in NFPA by both microarrays (Table S1) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) (Fig. 3), and because they have a greater fold of change in expression (>eightfold per microarrays; Table S1)
Summary
Pituitary adenomas (PAs) account for approximately 15% of intracranial primary tumors with a prevalence of close to one case per 1000 individuals (Daly et al, 2006; Fernandez et al, 2010). NFPAs do not cause, and cannot be diagnosed by, clinical hormone hypersecretion. Instead they are usually not diagnosed until these neoplasms grow rather large in size and begin to locally compress intracranial nerves and brain tissues, leading to symptoms. Despite a consistent level of research interest, our understanding of the molecular mechanisms that cause NFPA remains poor. This is partly evidenced by the fact that no clearly effective medications are currently available for NFPA, and that no molecular markers are currently established to diagnose NFPA before neurological symptoms occur. Identification of molecular players for NFPA tumorigenesis appears both critical and timely
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