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Non-syndromic tooth agenesis (NSTA) is one of the most common dental abnormalities. MiRNAs participated in the craniofacial and tooth development. Therefore, single nucleotide polymorphisms (SNPs) in miRNA genes may contribute to the susceptibility of non-syndromic tooth agenesis. Here, a total of 625 non-syndromic tooth agenesis cases and 1,144 healthy controls were recruited, and four miRNA SNPs (miR-146a /rs2910164, miR-196a2 /rs11614913, pre-miR-605 /rs2043556, pre-miR-618 /rs2682818) were genotyped by the TaqMan platform. Rs2043556 showed nominal associations with risk of non-syndromic tooth agenesis (P Add = 0.021) in the overall analysis, as well as upper lateral incisor agenesis (P Add = 0.047) and lower incisor agenesis (P Add = 0.049) in the subgroup analysis. Notably, its significant association with upper canine agenesis was observed (P Add = 0.0016). Rs2043556 affected the mature of miR-605-3p and miR-605-5p while dual-luciferase report analysis indicated that MDM2 was the binding target of miR-605-5p. Our study indicated that pre-miR-605 rs2043556 was associated with risk of non-syndromic tooth agenesis. [ABSTRACT FROM AUTHOR]

Background & Aims: Insulin resistance is strongly associated with non‐alcoholic fatty liver disease, a chronic, obesity–related liver disease. Increased endoplasmic reticulum (ER) stress plays an important role in the development of insulin resistance. In this study, we investigated the roles of miRNAs in regulating ER stress in the liver of rats with obesity. Methods: We used miRNA microarray to determine the miRNA expression profiles in the liver of rats fed with a high fat diet (HFD). We used prediction algorithms and luciferase reporter assay to identify the target gene of miRNAs. To overexpress the miRNA miR‐30b or inhibit miR‐30b rats were injected with lentivirus particles containing PGLV3‐miR‐30b or PGLV3‐miR‐30b antimiR through tail vein. Hepatic steatosis was measured using transient elastography in human subjects. Results: Our data showed that miR‐30b was markedly up‐regulated in the liver of HFD–treated rats. Bioinformatic and in vitro and in vivo studies led us to identify sarco(endo)plasmic reticulum Ca2+‐ATPase 2b (SERCA2b), as a novel target of miR‐30b. Overexpression of miR‐30b induced ER stress and insulin resistance in rats fed with normal diet, whereas inhibition of miR‐30b by miR‐30b antimiR suppressed ER stress and insulin resistance in HFD–treated rats. Finally, our data demonstrated that there was a positive correlation between serum miR‐30b levels and hepatic steatosis or homoeostasis model assessment of insulin resistance (HOMA‐IR) in human subjects. Conclusions: Our findings suggest that miR‐30b represents not only a potential target for the treatment of insulin resistance, but also a non‐invasive disease biomarker of NAFLD. [ABSTRACT FROM AUTHOR]

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in protecting against distinct brain damages, including ischemia. Our previous data have shown that the protein level of PPARγ is increased in the cortex after middle cerebral artery occlusion (MCAO); PPARγ up-regulation contributes to PPARγ activation and is effective in reducing ischemic damage to brain. However, the regulatory mechanism of PPARγ after focal cerebral ischemia in rats is still unclear. In this study, we evaluated the effect of microRNA on PPARγ in rats subjected to MCAO. Methods: Focal cerebral ischemia was established by surgical middle cerebral artery occlusion; the protein level of PPARγ was detected by Western blotting; the level of microRNA-383 (miR-383) was quantified by real-time PCR; the neurological outcomes were defined by infarct volume and neurological deficits. Luciferase assay was used to identify the luciferase activities of PPARγ and miR-383. Results: We showed here that miR-383 level was down-regulated in the ischemic hemisphere of rats 24h after MCAO. Overexpression of miR-383 by miR-383 agomir increased infarct volume and aggravated neurological damage. Administration of miR-383 antagomir had the opposite effects. Furthermore, we found that PPARγ protein was down-regulated by miR-383 overexpression, and up-regulated by miR- 383 inhibition both in rat model of MCAO and in primary culture cells. Finally, we found that miR-383 suppressed the luciferase activity of the vector carrying the 3'UTR of PPARγ, whereas mutation of the binding sites relived the repressive effect of miR-383. Conclusion: Our study demonstrated that miR-383 may play a key role in focal cerebral ischemia by regulating PPARγ expression at the post-transcriptional level, and miR-383 may be a potential therapeutic target for stroke. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53-MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that involved in a wide range of biological processes including differentiation, proliferation, and apoptosis. A polymorphism G>C (rs2910164) is located in the stem region opposite to the mature miR-146a sequence. In our study, we investigated whether rs2910164 is associated with the risk of colorectal cancer (CRC) in a Chinese population. We genotyped the rs2910164 polymorphism using TaqMan method and evaluated the association with CRC risk in a case-control study, including 1,147 CRC patients and 1,203 cancer-free controls. Logistic regression models were used to assess the genetic effects on the development of CRC. Overall, we found that rs2910164 was significantly associated with the reduced CRC risk [GC/CC versus GG: adjusted odds ratio (OR) = 0.78, 95 % confidence intervals (CIs) = 0.66-0.93]. In the stratification analysis, this decreased risk was also pronounced among non-smokers (0.75, 0.61-0.93), non-drinkers (0.77, 0.63-0.94), and no family history of cancer (0.79, 0.65-0.95). Furthermore, GC/CC genotypes were associated with reduced CRC susceptibility in intermediate differentiated CRC (0.75, 0.62-0.90), and similar effect was observed in patients with the advanced stage tumor (Dukes C and D) (0.76, 0.61-0.93). In conclusion, our results suggest that miR-146a rs2910164 may contribute to the susceptibility to CRC in a Chinese population. Further larger population-based prospective and functional studies are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Much evidence show that over-expression of epidermal growth factor receptor (EGFR) plays an important role in regulating carcinogenesis. Genetic variations in 3′ untranslated region (3′UTR) of gene have been reported to affect gene expression by interfering with microRNAs (miRNAs), which are thought to function as either tumour suppressors or oncogenes by binding to their target mRNA. In this study, we investigated the association between the EGFR 3′UTR 774T>C polymorphism and bladder cancer risk. We used the TaqMan technology to genotype this genetic variant in a hospital-based case–control study of 908 bladder cancer patients and 1239 controls in a Chinese population. We found that the 774CC genotype was associated with a statistically significantly increased risk of bladder cancer [adjusted odds ratio = 1.29, 95% confidence interval = 1.05–1.58], compared with the 774TT/TC genotype, and this increased risk was more pronounced among subgroups of age > 65 years, non-smokers and patients’ tumour invasive stage. Furthermore, luciferase assays in T24 cell showed that EGFR 3′UTR 774 T to C substitution could increase the expression of EGFR, which was consistent with the association study finding. Additionally, we also provide evidence that 774T>C polymorphism increasing EGFR expression was not regulated by hsa-miR-214 binding. These findings suggested that EGFR 3′UTR 774T>C polymorphism may contribute to susceptibility to bladder cancer. [ABSTRACT FROM PUBLISHER]

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC. [ABSTRACT FROM AUTHOR]

MicroRNAs are a class of short, noncoding RNAs that are ubiquitous modulators of gene expression, with roles in development, homeostasis, and disease. Engineered microRNAs are now frequently used as regulatory modules in synthetic biology. Moreover, synthetic gene circuits equipped with engineered microRNA targets with perfect complementarity to endogenous microRNAs establish an interface with the endogenous milieu at the single-cell level. The function of engineered microRNAs and sensor systems is typically optimized through extensive trial-and-error. Here, using a combination of synthetic biology experimentation in human embryonic kidney cells and quantitative analysis, we investigate the relationship between input genetic template abundance, microRNA concentration, and output under microRNA control. We provide a framework that employs the complete operational landscape of a synthetic gene circuit and enables the stepwise development of mathematical models. We derive a phenomenological model that recapitulates experimentally observed nonlinearities and contains features that provide insight into the microRNA function at various abundances. Our work facilitates the characterization and engineering of multi-component genetic circuits and specifically points to new insights on the operation of microRNAs as mediators of endogenous information and regulators of gene expression in synthetic biology. Synthetic biology: microRNA-based regulation MicroRNAs are increasingly important regulatory modules in genetic circuits. To probe their versatile nature, a systems and synthetic biology research team led by Dr. Leonidas Bleris at the University of Texas at Dallas, combined experiments and mathematical modeling to study the microRNA operational landscape. The team engineered custom genetic circuits that contain microRNA-based regulation and introduced an analytical strategy, that includes clustering and superposition of discrete experiments, to produce a "bird's-eye view" perspective. The team then developed mathematical models with informative features and predictive value. One feature highlighted in this work correlates the function of a microRNA to its concentration and the genetic circuit abundance. The results of this work may help towards rationally utilizing microRNAs in engineered gene circuits. [ABSTRACT FROM AUTHOR]

Purpose:miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk. Experimental Design:We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs. Results:We found that rs10719T>C polymorphism located in 3’ untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein. Conclusions:Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3’UTR. [ABSTRACT FROM AUTHOR]

Background and aims Long non-coding RNA (lncRNA) MEG3 has proven to be an important regulator involved in the pathogenesis and development of various human diseases. However, the functional involvement of MEG3 in postmenopausal osteoporosis (PMOP) and its mechanism is still unclear. Methods Bone marrow mesenchymal stem cells (BMSCs) were isolated and cultured from mouse pathologic models and patients with PMOP, respectively. The expression of MEG3 and miR-133a-3p in BMSCs was detected using qRT-PCR. The recombinant expression vector was constructed and transfected into BMSCs to regulate the endogenous expression of MEG3 and miR-133a-3p. The mineralized nodules formation, alkaline phosphatase (ALP) activity and Runx2, OCN, OPN expressions were used as specific markers for the differentiation of osteoblasts. Results The expressions of MEG3 and miR-133a-3p in BMSCs from PMOP were increased, and there was a positive correlation between MEG3 and miR-133a-3p expression in BMSCs. In the differentiation process from BMSCs to osteoblasts, the expressions of MEG3 and miR-133a-3p were markedly decreased, and MEG3 overexpression reversed the osteogenic induction-mediated downregulation of miR-133a-3p, which was accompanied by significant decline in SLC39A1 expression. Furthermore, miR-133a-3p silencing or upregulation eliminated the effects of MEG3 on the osteogenic differentiation of BMSCs through direct binding. Conclusions The research indicated that MEG3 regulated the expression of miR-133a-3p, and inhibited the osteogenic differentiation of BMSCs induced PMOP. [ABSTRACT FROM AUTHOR]