Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer

Abstract

BackgroundNon-coding RNAs (ncRNAs) are emerging as key regulators of many cellular processes in both physiological and pathological states. Moreover, the constant discovery of new non-coding RNA species suggests that the study of their complex functions is still in its very early stages. This variegated class of RNA species encompasses the well-known microRNAs (miRNAs) and the most recently acknowledged long non-coding RNAs (lncRNAs). Interestingly, in the last couple of years, a few studies have shown that some lncRNAs can act as miRNA sponges, i.e. as competing endogenous RNAs (ceRNAs), able to reduce the amount of miRNAs available to target messenger RNAs (mRNAs).ResultsWe propose a computational approach to explore the ability of lncRNAs to act as ceRNAs by protecting mRNAs from miRNA repression. A seed match analysis was performed to validate the underlying regression model. We built normal and cancer networks of miRNA-mediated sponge interactions (MMI-networks) using breast cancer expression data provided by The Cancer Genome Atlas.ConclusionsOur study highlights a marked rewiring in the ceRNA program between normal and pathological breast tissue, documented by its “on/off” switch from normal to cancer, and vice-versa. This mutually exclusive activation confers an interesting character to ceRNAs as potential oncosuppressive, or oncogenic, protagonists in cancer. At the heart of this phenomenon is the lncRNA PVT1, as illustrated by both the width of its antagonist mRNAs in normal-MMI-network, and the relevance of the latter in breast cancer. Interestingly, PVT1 revealed a net binding preference towards the mir-200 family as the bone of contention with its rival mRNAs.

Noncoding RNAs in breast cancer

“…Moreover, we also recently showed that the lincRNA-RoR serves as a ceRNA to suppress the inhibitory effect of miR-145 on triple-negative breast cancer invasiveness through targeting of ARF6 [93]. Using computational analysis, Paci et al [205] showed that the sponge interaction between ceRNAs and mRNAs in normal breast epithelium is altered in breast cancer, suggesting that dysregulation of ceRNAs may play a significant role in breast tumorigenesis.…”

The Interaction Between MiR-141 and lncRNA-H19 in Regulating Cell Proliferation and Migration in Gastric Cancer

“…Poliseno [5] previously proposed a competing endogenous RNA (ceRNA) hypothesis, which was supported by numerous evidences. In a recent paper, Paci et al [6] proposed a computational analysis able to identify ceRNA interactions between long non-coding RNAs and messenger RNAs in human breast cancer. The model described a complex post-transcriptional regulatory network mediated by miRNAs: by sharing one or more miRNA response elements (MRE), protein-coding and non-coding RNAs compete for binding to miRNAs and then regulate each other's expression.…”

LncRNAs: Bridging environmental sensing and gene expression

“…19 Histone modifying enzymes and nucleosome remodeling proteins that interact with lncRNAs include G9a, 20 LSD1, 21 PRC2, 21,22 SWI/SNF, 23 and MLL, 24 indicating a diversity of interactions. LncRNAs have also been described as miRNA sponges, 25 facilitators of cytoplasmic mRNA decay, 26 and remodelers of the 3D chromatin architecture, 27 indicating a broad array of activities. In addition to biochemical diversity, a common theme for lncRNA function is temporal control of gene expression, regulating cellular programs that require highly specific and well timed responses to extracellular stimuli.…”