Endogenous miRNA and Target Concentrations Determine Susceptibility to Potential ceRNA Competition

Bosson, Andrew; Zamudio, Jesse R.; Sharp, Phillip A.

doi:10.1016/j.molcel.2014.09.018

Cited by 378 publications

(431 citation statements)

References 57 publications

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“…Hence, a better understanding of the role of competing endogenous RNAs (ceRNAs) in miRNA mechanisms is urgently needed. We predict such a phenomenon might take place only at high TPM, given the preferential interaction of a miRNA with high-affinity targets and the reduction of the effective target pool, as previously observed (Bosson et al 2014).…”

Section: High Complementary Targets and Enzymatic Activities Are Detesupporting

confidence: 74%

“…Although these correlations are strong, more direct evidence will be required to demonstrate that the behavior of "fast" miRNAs depends on the level of their 3 ′ complementary targets. Of note, several studies pointed out the existence of a threshold in target repression that depends on miRNA expression and target abundance (Mukherji et al 2011;Mullokandov et al 2012;Bosson et al 2014), suggesting that the activity of a miRNA on its target decreases sharply at high TPM ratios. A relevant implication of our study is the theoretical possibility to switch from "high" to "low" TPM and thus modify the activity and the decay of miRNAs.…”

Section: High Complementary Targets and Enzymatic Activities Are Detementioning

confidence: 99%

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Degradation dynamics of microRNAs revealed by a novel pulse-chase approach

et al. 2016

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The regulation of miRNAs is critical to the definition of cell identity and behavior in normal physiology and disease. To date, the dynamics of miRNA degradation and the mechanisms involved in remain largely obscure, in particular, in higher organisms. Here, we developed a pulse-chase approach based on metabolic RNA labeling to calculate miRNA decay rates at genome-wide scale in mammalian cells. Our analysis revealed heterogeneous miRNA half-lives, with many species behaving as stable molecules (T 1/2 > 24 h), while others, including passenger miRNAs and a number (25/129) of guide miRNAs, are quickly turned over (T 1/2 = 4-14 h). Decay rates were coupled with other features, including genomic organization, transcription rates, structural heterogeneity (isomiRs), and target abundance, measured through quantitative experimental approaches. This comprehensive analysis highlighted functional mechanisms that mediate miRNA degradation, as well as the importance of decay dynamics in the regulation of the miRNA pool under both steady-state conditions and during cell transitions.

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Section: High Complementary Targets and Enzymatic Activities Are Detesupporting

confidence: 74%

Section: High Complementary Targets and Enzymatic Activities Are Detementioning

confidence: 99%

Degradation dynamics of microRNAs revealed by a novel pulse-chase approach

et al. 2016

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“…In HCC, HULC functions as an endogenous sponge that suppresses the activity of miR-372 (17). Meanwhile, emerging studies showed that ceRNAs cannot alter miRNA function in vivo (36,37). They demonstrated that it is difficult to achieve sufficiently high expression of a ceRNA to significantly derepress the mRNAs regulated by that miRNA in vivo.…”

Section: Discussionmentioning

confidence: 99%

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

et al. 2015

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Despite progress in the diagnostics and treatment of hepatocellular carcinoma (HCC), its prognosis remains poor. In this study, we globally assessed long noncoding RNAs (lncRNA) for contributions to HCC using publicly available microarray data, in vitro and in vivo assays. Here, we report that ZFAS1, encoding a lncRNA that is frequently amplified in HCC, is associated with intrahepatic and extrahepatic metastasis and poor prognosis of HCC. ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16. Conversely, ZFAS1 activated ZEB1, MMP14, and MMP16 expression, inhibiting these effects of miR-150. Our results establish a function for ZFAS1 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of HCC. Cancer Res; 75(15); 3181-91. Ó2015 AACR.

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“…Thus, BRLF1/BZLF1, and BAD do not appear to exert a ceRNA effect on each other. ceRNA effects are argued to be induced only in miRNA families with low total miRNA-to-target ratios (43). Furthermore, it was recently suggested that modulation of miRNA target abundance is unlikely to cause significant effects on gene expression and metabolism through a ceRNA effect, based on stoichiometric analysis of miR-122 and its well-known targets (44).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

Kim

Choi

Lee

2016

J Virol

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Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

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Endogenous miRNA and Target Concentrations Determine Susceptibility to Potential ceRNA Competition

Cited by 378 publications

References 57 publications

Degradation dynamics of microRNAs revealed by a novel pulse-chase approach

Degradation dynamics of microRNAs revealed by a novel pulse-chase approach

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

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