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Role of microRNAs in oncogenesis: Insights from computational and systems-level modeling approaches

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Abstract

MicroRNAs (miRNAs) are short (~22 nucleotides) non-coding RNAs that are often intricately integrated into the regulatory networks of various cellular processes and govern the cell fate decision making events associated with oncogenesis by regulating the gene expression through post-transcriptional modifications. miRNAs repress the target genes by either degrading the target mRNA or by inhibiting the process of translation. However, mathematical and computational modeling of miRNA-mediated target gene regulation in various cellular network motifs suggests that miRNAs play a much more complex role in cellular decision-making events. In this review, we give an overview of the quantitative insights obtained from such kind of mathematical modeling of miRNA mediated gene regulation by highlighting the various factors associated with miRNA regulation that are pivotal in diversifying the cell fate decisions related to oncogenesis. Intriguingly, recent experiments suggest that miRNAs can even upregulate the translation of the target protein under certain circumstances, which may lead to more complexities in miRNA-mediated gene regulations. We discussed possible avenues to explore such unusual biological observations related to miRNA’s that can be modeled to get a detailed understanding of the influence of miRNAs in the context of oncogenesis.

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Transcription in several organisms from certain bacteria to humans has been observed to be stochastic in nature: toggling between active and inactive states. Periods of active nascent RNA synthesis known as bursts represent individual gene activation events in which multiple polymerases are initiated. Therefore, bursting is the single locus illustration of both gene activation and repression. Although transcriptional bursting was originally observed decades ago, only recently have technological advances enabled the field to begin elucidating gene regulation at the single-locus level. In this review, we focus on how biochemical, genomic, and single-cell data describe the regulatory steps of transcriptional bursts. Expected final online publication date for the Annual Review of Biochemistry, Volume 89 is June 22, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Article
Biochemical prediction of miRNA targeting MicroRNAs (miRNAs) regulate most human messenger RNAs and play essential roles in diverse developmental and physiological processes. Correctly predicting the function of each miRNA requires a better understanding of miRNA targeting efficacy. McGeary et al. measured binding affinities between six miRNAs and synthetic targets, built a biochemical model of miRNA-mediated repression, and expanded it to all miRNAs using a convolutional neural network. This approach offers insights into miRNA targeting and enables more accurate prediction of intracellular miRNA repression efficacy than previous algorithms. Science , this issue p. eaav1741
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Noncoding RNAs (ncRNAs) play critical roles in essential cell fate decisions. However, the exact molecular mechanisms underlying ncRNA-mediated bistable switches remain elusive and controversial. In recent years, systematic mathematical and quantitative experimental analyses have made significant contributions on elucidating the molecular mechanisms of controlling ncRNA-mediated cell fate decision processes. In this chapter, we review and summarize the general framework of mathematical modeling of ncRNA in a pedagogical way and the application of this general framework on real biological processes. We discuss the emerging properties resulting from the reciprocal regulation between mRNA, miRNA, and competing endogenous mRNA (ceRNA), as well as the role of mathematical modeling of ncRNA in synthetic biology. Both the positive feedback loops between ncRNAs and transcription factors and the emerging properties from the miRNA-mRNA reciprocal regulation enable bistable switches to direct cell fate decision.
Article
The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation. In contrast, the importance of the expression levels of E2F1 itself in dictating the downstream phenotypes has not been rigorously studied, partly due to the limited resolution of traditional population-level measurements. Here, through single-cell quantitative analysis, we demonstrate that E2F1 expression levels have a critical role in determining the fate of individual cells. Low levels of exogenous E2F1 promote proliferation, moderate levels induce G1, G2 and mitotic cell cycle arrest, and very high levels promote apoptosis. These multiple anti-proliferative mechanisms result in a strong selection pressure leading to rapid elimination of E2F1-overexpressing cells from the population. RNA-sequencing and RT-PCR revealed that low levels of E2F1 are sufficient to induce numerous cell cycle-promoting genes, intermediate levels induce growth arrest genes (i.e., p18, p19 and p27), whereas higher levels are necessary to induce key apoptotic E2F1 targets APAF1, PUMA, HRK and BIM. Finally, treatment of a lung cancer cell line with a proteasome inhibitor, MLN2238, resulted in an E2F1-dependent mitotic arrest and apoptosis, confirming the role of endogenous E2F1 levels in these phenotypes. The strong anti-proliferative activity of moderately overexpressed E2F1 in multiple cancer types suggests that targeting E2F1 for upregulation may represent an attractive therapeutic strategy in cancer.
Article
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs, which regulate complementary mRNAs by inducing translational repression and mRNA decay. Although this dual repression system seems to operate in both animals and plants, genetic and biochemical studies suggest that the mechanism underlying the miRNA-mediated silencing is different in the two kingdoms. Here, we review the recent progress in our understanding of how miRNAs mediate translational repression and mRNA decay, and discuss the contributions of the two silencing modes to the overall silencing effect in both kingdoms.
Article
MicroRNAs (miRNAs) repress the expression of many genes in metazoans by accelerating messenger RNA degradation and inhibiting translation, thereby reducing the level of protein. However, miRNAs only slightly reduce the mean expression of most targeted proteins, leading to speculation about their role in the variability, or noise, of protein expression. We used mathematical modeling and single-cell reporter assays to show that miRNAs, in conjunction with increased transcription, decrease protein expression noise for lowly expressed genes but increase noise for highly expressed genes. Genes that are regulated by multiple miRNAs show more-pronounced noise reduction. We estimate that hundreds of (lowly expressed) genes in mouse embryonic stem cells have reduced noise due to substantial miRNA regulation. Our findings suggest that miRNAs confer precision to protein expression and thus offer plausible explanations for the commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes.
Article
Post-transcriptional gene regulation (PTGR) of mRNA turnover, localization and translation is mediated by microRNAs (miRNAs) and RNA-binding proteins (RBPs). These regulators exert their effects by binding to specific sequences within their target mRNAs. Increasing evidence suggests that competition for binding is a fundamental principle of PTGR. Not only can miRNAs be sequestered and neutralized by the targets with which they interact through a process termed 'sponging', but competition between binding sites on different RNAs may also lead to regulatory crosstalk between transcripts. Here, we quantitatively model competition effects under physiological conditions and review the role of endogenous sponges for PTGR in light of the key features that emerge.
Article
Despite their clear importance as a class of regulatory molecules, pinpointing the relevance of individual miRNAs has been challenging. Studies querying miRNA functions by overexpressing or silencing specific miRNAs have yielded data that are often at odds with those collected from loss-of-functions models. In addition, knockout studies suggest that many conserved miRNAs are dispensable for animal development or viability. In this review, we discuss these observations in the context of our current knowledge of miRNA biology and review the evidence implicating miRNA-mediated gene regulation in the mechanisms that ensure biological robustness. Copyright © 2014 Elsevier Ltd. All rights reserved.
Article
The emergence of microRNAs has been one of the defining developments in cancer biology over the past decade, and the explosion of knowledge in this area has brought forward new diagnostic and therapeutic opportunities. The importance of microRNAs in cancer has been underlined by the identification of alterations in microRNA target binding sites and the microRNA processing machinery in tumor cells. Clinical trials utilizing microRNA profiling for patient prognosis and clinical response are now underway, and the first microRNA mimic entered the clinic for cancer therapy in 2013. In this article we review the potential applications of microRNAs for the clinical assessment of patient outcome in cancer, as well as in cancer monitoring and therapy.
Article
Recent studies have reported that competitive endogenous RNAs (ceRNAs) can act as sponges for a microRNA (miRNA) through their binding sites and that changes in ceRNA abundances from individual genes can modulate the activity of miRNAs. Consideration of this hypothesis would benefit from knowing the quantitative relationship between a miRNA and its endogenous target sites. Here, we altered intracellular target site abundance through expression of an miR-122 target in hepatocytes and livers and analyzed the effects on miR-122 target genes. Target repression was released in a threshold-like manner at high target site abundance (≥1.5 × 10(5) added target sites per cell), and this threshold was insensitive to the effective levels of the miRNA. Furthermore, in response to extreme metabolic liver disease models, global target site abundance of hepatocytes did not change sufficiently to affect miRNA-mediated repression. Thus, modulation of miRNA target abundance is unlikely to cause significant effects on gene expression and metabolism through a ceRNA effect.
Article
Poly(A) tails enhance the stability and translation of most eukaryotic messenger RNAs, but difficulties in globally measuring poly(A)-tail lengths have impeded greater understanding of poly(A)-tail function. Here we describe poly(A)-tail length profiling by sequencing (PAL-seq) and apply it to measure tail lengths of millions of individual RNAs isolated from yeasts, cell lines, Arabidopsis thaliana leaves, mouse liver, and zebrafish and frog embryos. Poly(A)-tail lengths were conserved between orthologous mRNAs, with mRNAs encoding ribosomal proteins and other 'housekeeping' proteins tending to have shorter tails. As expected, tail lengths were coupled to translational efficiencies in early zebrafish and frog embryos. However, this strong coupling diminished at gastrulation and was absent in non-embryonic samples, indicating a rapid developmental switch in the nature of translational control. This switch complements an earlier switch to zygotic transcriptional control and explains why the predominant effect of microRNA-mediated deadenylation concurrently shifts from translational repression to mRNA destabilization.
Article
Transcription factors (TFs) and microRNAs (miRNAs) can jointly regulate target gene expression in the forms of feed-forward loops (FFLs) or feedback loops (FBLs). These regulatory loops serve as important motifs in gene regulatory networks and play critical roles in multiple biological processes and different diseases. Major progress has been made in bioinformatics and experimental study for the TF and miRNA co-regulation in recent years. To further speed up its identification and functional study, it is indispensable to make a comprehensive review. In this article, we summarize the types of FFLs and FBLs and their identified methods. Then, we review the behaviors and functions for the experimentally identified loops according to biological processes and diseases. Future improvements and challenges are also discussed, which includes more powerful bioinformatics approaches and high-throughput technologies in TF and miRNA target prediction, and the integration of networks of multiple levels.
Article
MicroRNAs (miRNAs) are emerging as a class of small regulated RNAs, and the alterations of miRNAs are implicated in the initiation and progression of human cancers. Our study shows that inhibition of miR-20a in OVCAR3 ovarian cancer cell line could suppress, whereas overexpression of miR-20a could enhance cell long-term proliferation and invasion. We also confirmed amyloid precursor protein (APP) as a direct target gene of miR-20a. Furthermore, suppression of APP expression could also promote ovarian cancer cell proliferation and invasion, which is consistent with the results of miR-20a overexpression. Therefore, we concluded that the regulation of APP is an important mechanism for miR-20a to promote proliferation and invasion in ovarian cancer cells.
Article
Argonaute (Ago) proteins have been demonstrated to be widely expressed and involved in post-transcriptional gene silencing and thus play key roles in carcinogenesis. Nevertheless, little is known about the specific role of Ago2 in gastric cancer (GC). Thus, we aimed to study the expression of Ago2 in 363 primary GC, 8 corresponding lymph node metastases and 10 non-neoplastic surrounding gastric epithelium tissues by immunohistochemical analyses and tissue microarray. The expression of Ago2 was also correlated with clinicopathological characteristics and HER-2 status. Ago2 expression levels in primary GC and corresponding lymph node metastases were significantly higher compared with healthy controls (P < 0.05). But, there was no difference of Ago2 between GC and its metastatic lymph node (P > 0.05). Ago2 up-regulation had no correlation with GC patients' age, tumor location, tumor size, gross morphology or tumor infiltration. However, we found that Ago2 was different between HER-2 positive and HER-2 negative groups (P = 0.044), which had been demonstrated to be related to GC prognosis. And there was a great correlation between Ago2 expression and the tumor differentiation (P = 0.007), lymph node invasion (P = 0.000) and clinical stage (P = 0.006). Interestingly, Ago2 was also correlated to patients' gender (P = 0.004), which may suggest a possible role of hormonal signal in the mechanisms of Ago2. Thus, our results suggested that up-regulation of Ago2 may play an important role in GC carcinogenesis and progression. Further studies on the cellular functions of Ago2 need to address these issues.
Article
microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
Article
miR-17-5p is abnormally expressed in various tumor types. The aim of this study was to investigate the expression level of miR-17-5p in serum of patients with lung cancer and to determine whether serum miR-17-5p expression is related to the prognosis of patients with lung cancer. RT-qPCR was used to examine expression of miRNA-17-5p in 20 pairs of lung cancer and adjacent normal tissues, and sera from 221 patients with lung cancer and 54 matched controls. The correlation of serum miR-17-5p with clinicopathological factors or prognosis of patients with lung cancer was analyzed. The expression level of miR-17-5p obviously increased in lung cancer tissues (P = 0.004). Furthermore, serum miR-17-5p expression also significantly increased in patients with lung cancer compared with healthy individuals (P = 0.03). The survival analysis showed that serum miR-17-5p expression was closely related to the survival of patients with lung cancer. Patients with high miR-17-5p expression had shorter survival times [hazard ratio (HR) = 1.767, 95 %CI 1.039-3.005, P = 0.035]. A lower expression level of serum miR-17-5p helps extend the survival of patients with lung cancer. Thus, miR-17-5p may be potential biomarker for prediction the prognosis in patients with lung cancer.