Identifying Complex lncRNA/Pseudogene–miRNA–mRNA Crosstalk in Hormone-Dependent Cancers

Abstract

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.

MALAT1 regulates PCT expression in sepsis patients through the miR‐125b/STAT3 axis

“…The competing endogenous RNA (ceRNA) hypothesis is proposed as an essential post‐transcriptional regulation mechanism. LncRNA, pseudogene, mRNA, and other endogenous RNAs contain some identical miRNA binding sites, which can competitively bind common miRNAs to weaken their inhibition of target genes, thereby improving the expression level of target genes and regulating cell life activities 17 . This new hypothesis has gradually become a research hotspot and has been confirmed in various signaling pathways.…”

A supervised machine learning approach identifies gene‐regulating factor‐mediated competing endogenous RNA networks in hormone‐dependent cancers

“…Our previous bioinformatic study identified shared ceRNAs (both lncRNAs and mRNAs) across PRAD, BRCA, COLCA and UCEC, considering miRNAs as the only gene regulator in the ceRNA network 6 . This study has integrated conventional ceRNA networks with DM, TF and CNA data using a machine‐learning approach, ‘Cancerin.’ According to our results, DM, TF and CNA significantly have cut‐off shared ceRNAs across HD cancers found from the conventional methods.…”

“…We used three thresholds as follows: the hypergeometric test p < 0.05, the Pearson correlation coefficient of lncRNA–mRNA or mRNA–mRNA pairs > 0.40, and the adjusted p of mscor < 0.05 to infer ceRNA candidates of each HD cancer. We have extensively described these methods in our previous conventional ceRNA network analyses paper 6 …”

“…We have extensively described these methods in our previous conventional ceRNA network analyses paper. 6 Identifying ceRNAs common among multiple HD cancer types may assist in understanding their shared molecular pathogenesis and drug repositioning. Therefore, we evaluated shared ceRNA pairs (lncRNA-mRNA or mRNA-mRNA) among HD cancer types.…”

“…The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs (mRNAs) and other RNA transcripts, such as lncRNAs and pseudogenes, can act as natural miRNA sponges 5 . These RNAs influence each other's expression levels by competing for the same pool of miRNAs through miRNA response elements (MREs) on their target transcripts, thereby modulating gene expression and protein activity 6 . Crosstalk between ceRNAs through shared MREs represents a novel layer of gene regulation that plays an important role in the physiology and development of complex human diseases such as cancers.…”