Abstract
Pseudogenes are initially regarded as non-functional genomic fossils resulted from inactivating gene mutations during evolution. Far from being silent, pseudogenes are proved to regulate the expression of protein-coding genes through function as microRNA sponge in vivo. The aim of our study was to propose an integrative systems biology approach to identify disease pseudogenes base on competitive endogenous RNA (ceRNA) hypothesis. Here, we applied our method to lung adenocarcinoma (LUAD) RNASeq data from TCGA and identified 33 candidate pseudogenes. We described the characteristics of the candidate pseudogenes and performed functional enrichment. Through analyzing neighboring genes we found these pseudogenes were surrounded by tumor genes and may involve in tumor pathway. Furthermore, the DNA methylation analysis indicated that 21 pseudogenes co-methylated with their competitive mRNAs. In the co-methylated network, we discovered 6 differentially expressed pseudogenes, which we termed potential LUAD-associated pseudogenes. We further revealed that the 3 ceRNA triples (miR-21-5p-NKAPP1-PRDM11, miR-29c-3p-MSTO2P-EZH2 and miR-29c-3p-RPLP0P2-EZH2), whose high risk groups were associated with the poor prognosis of LUAD, may be considered as potential prognostic signatures. Moreover, by integrating target information of microRNA we also provided a new perspective for the discovery of potential small molecule drugs. This work may facilitate cancer research and serve as the basis for future efforts to understand the role of pseudogenes, develop novel biomarkers and improve knowledge of tumor biology.
Highlights
Pseudogenes, a sub-class of long non-coding RNAs that developed from protein-coding genes (PCGs) but have lost the ability to produce proteins, have long been described as non-functional genomic relicts of evolution [1]
We further revealed that the 3 competitive endogenous RNA (ceRNA) triples, whose high risk groups were associated with the poor prognosis of lung adenocarcinoma (LUAD), may be considered as potential prognostic signatures
To ensure the accuracy of prediction power, positive pseudogene-mRNA interactions was identified by strict criteria: (i) both of the mRNA and microRNA in each triple must be verified by disease databases; (ii) each possible mRNA-pseudogene pair must significantly share common microRNAs which can interact with both of them; (iii) only top correlated mRNA-pseudogene pairs, whose correlation coefficients www.impactjournals.com/oncotarget were higher than the threshold of the 90th percentile of the corresponding overall correlation distribution (PCC ≥ 0.259), were regarded as candidate pseudogene-mRNA interactions
Summary
Pseudogenes, a sub-class of long non-coding RNAs (lncRNAs) that developed from protein-coding genes (PCGs) but have lost the ability to produce proteins, have long been described as non-functional genomic relicts of evolution [1]. Far from being silent, pseudogenes participate in various biological activities, including being a part in the transcription process [2], or participating in the formation of small interfering RNA (siRNA) which regulated gene expression through RNA-interference pathway [3, 4]. Several studies implicate dysregulation of pseudogenes as contributing factor in human cancer, with early example such as KRASIP [5]. An increasing number of studies describe pseudogenes that act as critical effectors in cancer progression [6]. NANOG and OCT4 are essential transcription factors for the maintenance of pluripotency in embryonic stem cells [7, 8], while their pseudogenes, NANOGP1 and POU5F1P1, are aberrantly expressed in human cancers [9]. Florian et al had provided an evidence that the BRAF pseudogene acted as a competitive endogenous www.impactjournals.com/oncotarget
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