Due to the ceRNA theory, the competition between lncRNAs and miRNAs makes indirect regulation possible. In light of the role in regulating target genes, miRNAs can exercise the similar function to negatively regulate the expression of lncRNAs, and thus exert a series of biological effects in GC. Yan et al reported that MEG3 expression level was markedly reduced in both tissues and cell lines of GC, and further experiments found that transfection of MEG3 siRNA into cells could diminish the suppression of proliferation induced by overexpression of miR-148a, which suggested that miR-148a might decrease the expression of MEG3 by modulation of DNMT-1. Furthermore, another study found that upregulated H19 could promote the proliferation of GC cells by binding miR-675, which inversely inhibited the tumor suppressor gene RUNX1. The interaction between H19/miR-675 and RUNX1 may serve as novel targets in the tumorigenesis of GC.
Molecular mechanism of ceRNAs andclassification. (A) mRNAs, transcribed pseudogenes, lncRNAs andcirRNAs are able to function as competing endogenous RNAs. (B)Downregulation of ceRNAs results in increased availability of miRNAmolecules to bind to mRNA, thereby repressing protein translation.(C) Overexpression of ceRNA results in a reduction in free miRNAabundance, facilitating the derepression of mRNAs that containidentical MREs, thus increasing protein expression levels. ceRNA,competing endogenous RNA; mRNA, messenger RNA; lncRNA, longnon-coding RNA; cirRNA, circular RNA; miRNA, micro RNA; MRE, miRNAresponse element.
Oncotarget | Competing endogenous RNA networks in …
With the ever-expanding number of lncRNAs,increasing numbers of studies have focused on the roles of lncRNAsin epigenetic mechanisms and other biological processes (,).Notably, lncRNAs have begun to emerge as natural miRNA decoys,suggesting that they may function as ceRNAs at thepost-transcriptional regulatory level (–). Inparticular, the muscle-specific lncRNA LINCMD1 regulates muscledifferentiation by binding and sequestering miR-133 and miR-135(). Typically, these miRNAsnegatively regulate expression of the mastermind-like 1 (MAML1) andmyocyte enhancer factor 2C (MEF2C) transcription factors, whichinduce muscle-specific gene expression. Therefore, by sequesteringthese miRNAs, LINCMD1 functions as an miRNA decoy and activatesMAML1 and MEF2C. In addition, HULC, an lncRNA that has previouslybeen identified to be highly upregulated in liver cancer, acts asan endogenous sponge, downregulating the activity of a series ofmiRNAs, including miR-372 (). Theinhibition of miR-372 reduces translational repression of itstarget gene, PRKACB. Another lncRNA, H19, which possesses canonicaland non-canonical binding sites for the let-7 family of miRNAs, hasbeen demonstrated to modulate let-7 availability by competing withDICER and HMGA2 as a molecular sponge (). These studies indicated that lncRNAsmay be involved in post-transcriptional regulation by functioningas ceRNAs. Additional lncRNAs functioning as miRNA decoys will bediscussed in detail below.
Long noncoding RNA associated-competing endogenous RNAs …
The competing endogenous RNA (ceRNA) hypothesis was introduced. There is a new hypothesis about mRNA, pseudogene transcripts and long noncoding RNAs (lncRNAs) regulate each other’s expression by using microRNA response elements (MREs) to compete for the binding of microMRA (miRNA). To date, numbers lines of evidence in bioinformatics, cell biology and animal models from several famous laboratories have supported the ceRNA hypothesis. We also trace the history of the concept of ceRNA and discuss the molecular mechanisms of ceRNAs in cancers and their possible applications. In this review, we try to give readers a concise and reliable illustration on the mechanism, research approaches, and perspective of ceRNA in cancer.
Competing endogenous RNA in cancer: A new pattern …
ceRNA, competingendogenous RNA; mRNA, messenger RNA; miRNA, micro RNA; PI3K,phosphoinositide 3-kinase; HER2, human epidermal growth factorreceptor 2; ciRS-7, circular RNA sponge for miR-7.
| The competing endogenous RNA (ceRNA) hypothesis was introduced
The lncRNA, HOTAIR, was initially known for itseffects in primary breast tumors and breast cancer metastases,where enhanced HOTAIR expression promoted invasion and metastasis(). Recent studies also identifiedupregulated HOTAIR expression in gastric cancer (,).HOTAIR functions as a ceRNA, regulating the expression of humanepithelial growth factor receptor 2 (HER2) by competing formiR-331-3p. HOTAIR thus functions as an oncogene in gastricpathogenesis by inducing the activation of HER2 cell signalingnetworks (). This finding furthersupports the hypothesis that the ceRNA function of RNA transcriptsis of fundamental significance in oncogenic transformation.