Julie Bienertova-Vasku

Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer

•  Introduction •  Classification of miRNA‐related SNPs ‐  SNPs in miRNA processing machinery ‐  SNPs in pri‐, pre‐, mat‐miRNAs ‐  SNPs in miRNA‐binding sites •  MiRNA‐related SNPs and solid cancer ‐  Breast cancer ‐  Colorectal cancer ‐  Lung cancer ‐  Prostate cancer ‐  Renal cell carcinoma ‐  Cervical cancer ‐  Ovarian cancer ‐  Gastric cancer ‐  Bladder cancer ‐  Oesophageal cancer ‐  Hepatocellular carcinoma ‐  Head and neck cancer ‐  Thyroid cancer ‐  Glioma •  Conclusions and future directions

Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer.

AIM To investigate whether selected single nucleotide polymorphisms (SNPs) in miR-196a2, miR-27a and miR-146a genes are associated with sporadic colorectal cancer (CRC). METHODS In order to investigate the effect of these SNPs in CRC, we performed a case-control study of 197 cases of sporadic CRC and 212 cancer-free controls originating from the Central-European Caucasian population using TaqMan Real-Time polymerase chain reaction and allelic discrimination analysis. RESULTS The genotype and allele frequencies of SNPs were compared between the cases and the controls. None of the performed analysis showed any statistically significant results. CONCLUSION Our data suggest a lack of association between rs11614913, rs895819 and rs2910164 and colorectal cancer risk in the Central-European Caucasian population, a population with an extremely high incidence of sporadic colorectal cancer.

Muscle-specific microRNAs in skeletal muscle development

Proper muscle function constitutes a precondition for good heath and an active lifestyle during an individuals lifespan and any deviations from normal skeletal muscle development and its functions may lead to numerous health conditions including e.g. myopathies and increased mortality. It is thus not surprising that there is an increasing need for understanding skeletal muscle developmental processes and the associated molecular pathways, especially as such information could find further uses in therapy. The understanding of complex skeletal muscle developmental networks was broadened with the discovery of microRNA (miRNA) molecules. MicroRNAs are evolutionary conserved small non-coding RNAs capable of negatively regulating gene expression on a post-transcriptional level by means of miRNA-mRNA interaction. Several miRNAs expressed exclusively in muscle have been labeled myomiRs. MyomiRs represent an integral part of skeletal muscle development, i.e. playing a significant role during skeletal muscle proliferation, differentiation and regeneration. The purpose of this review is to provide a summary of current knowledge regarding the involvement of myomiRs in the individual phases of myogenesis and other aspects of skeletal muscle biology, along with an up-to-date list of myomiR target genes and their functions in skeletal muscle and miRNA-related therapeutic approaches and future prospects.

MicroRNAs in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment

Pulmonary arterial hypertension (PAH) is a severe and increasingly prevalent disease, manifested by the maladaptation of pulmonary vasculature, which consequently leads to right heart failure and possibly even death. The development of PAH is characterized by specific functional as well as structural changes, primarily associated with the aberrant function of the pulmonary artery endothelial cells, smooth muscle cells, and vascular fibroblasts. MicroRNAs constitute a class of small ≈22-nucleotides-long non-coding RNAs that post-transcriptionally regulate gene expression and that may lead to significant cell proteome changes. While the involvement of miRNAs in the development of various diseases--especially cancer--has been reported, numerous miRNAs have also been associated with PAH onset, progression, or treatment responsiveness. This review focuses on the role of microRNAs in the development of PAH as well as on their potential use as biomarkers and therapeutic tools in both experimental PAH models and in humans. Special attention is given to the roles of miR-21, miR-27a, the miR-17-92 cluster, miR-124, miR-138, the miR-143/145 cluster, miR-150, miR-190, miR-204, miR-206, miR-210, miR-328, and the miR-424/503 cluster, specifically with the objective of providing greater insight into the pervasive roles of miRNAs in the pathogenesis of this deadly condition.

The role of microRNAs in mitochondria in cancer

Reprogramming of the energy metabolism in cancer cell presents progressive field of cancer research. This feature is associated mainly with the mitochondria, which is major energy source of eukaryotic cells. These organelles are essential to the cell homeostasis maintenance, play an important role in intrinsic apoptotic pathway and their dysfunction is associated with multiple diseases including cancer. Recently, it was described that microRNAs (miRNAs) regulate important signaling pathways in mitochondria and many of these miRNAs are deregulated in various cancers. Here we summarize current knowledge about miRNAs involved in mitochondrial functioning with focus on cellular energy metabolism, apoptosis and mitophagy.

Identification of MicroRNAs Regulated by Isothiocyanates and Association of Polymorphisms Inside Their Target Sites with Risk of Sporadic Colorectal Cancer

Sporadic colorectal cancer (CRC) is a typical multifactorial disease. Isothiocyanates (ITC) have been recently shown to inhibit development of CRC in many experimental models. MicroRNAs (miRNAs) are short noncoding RNAs that posttranscriptionally regulate gene expression through binding to 3′ untranslated regions (3′UTR) of target mRNAs. MiRNAs are regulated by natural agents, ITCs included. In our study, using global expression profiling based on TaqMan Low-Density Arrays, we identified 3 common miRNAs (miR-155, miR-23b, miR-27b) regulated by ITCs (sulforaphane, iberin) in colonic epithelial cell lines NCM460 and NCM356. In silico predictions allowed us to find 9 relevant single nucleotide polymorphisms (SNPs) localized within the 3′UTRs of genes (AGTR1, TNFAIP2, PRKCB, HSPA9, RABGAP1, DICER1, ADAM19, VWA5A, and SIRT5) targeted by these ITC-related miRNAs. Finally, we observed that homozygous CC genotype of DICER1, rs1057035, was significantly associated with decreased risk of CRC (odds ratio = 0.49; 95% confidence interval: 0.25–0.95, P = 0.036) when compared to TT homozygote genotype; also, the C allele tended to have a protective effect (P = 0.072). This study showed that miRNAs could be involved in chemoprotective effects of natural agents; their function alteration through SNPs in their binding sites and flanking regions presents a new class of CRC risk factors.

Visfatin and its role in obesity development.

Visfatin, a product of PBEF gene, is an adipocytokine that harbours strong insulin-mimetic activity and it has been reported previously to associate with obesity. Recent reports also provide evidence that Visfatin has also important intracellular effects as it is homologous with nicotinamide phosphoribosyltransferase (NAMPT). In this review, we summarize the main documented effects of Visfatin on metabolism in humans, with special emphasis put on the pathways associated with obesity.

Common polymorphisms in GSTM1, GSTT1, GSTP1, GSTA1 and susceptibility to colorectal cancer in the Central European population

BackgroundCentral Europe presents with the highest incidence of sporadic colorectal cancer (CRC) worldwide. As sporadic CRC represents a typical multifactorial disease, it is characterized by intense interaction of the genetic background with the environment. Glutathione S-transferases could act as attractive susceptibility genes for CRC, as they are directly involved in conjugation between glutathione and chemotherapeutics, environmental pollutants and a wide spectrum of xenobiotics.MethodsIn this study, we investigated associations of polymorphisms in glutathione S-transferases (GSTs) genes, that is GSTA1, GSTT1, GSTM1 and GSTP1, with CRC in a total of 197 cases and 218 controls originating from the Czech Central European population. Polymorphisms were assessed by polymerase chain reaction/restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction.ResultsNone of investigated polymorphisms showed any associations with CRC, with the exception of GSTP1; where the heterozygote genotype Ile105Val was associated with decreased risk of CRC (P = 0.043).ConclusionsThe frequencies observed in our study are in accordance with those from other European Caucasian populations. Based on our studies, examined variability in GST genes is not a major determinant of CRC susceptibility in the Central European population.

No association of defined variability in leptin, leptin receptor, adiponectin, proopiomelanocortin and ghrelin gene with food preferences in the Czech population.

Abstract Background: Previously, it has been reported that mutations in the genes encoding for adipokines may be associated with impaired food intake and may serve as potential obesity biomarkers. The aim of this study was to investigate the possible associations of defined variability in leptin, leptin receptor, adiponectin, proopiomelanocortin and ghrelin genes with food preferences in the obese and non-obese Czech population and evaluate their potential as the obesity susceptibility genes. Patients and Methods: Using PCR followed by restriction analysis, we studied 185 volunteers. Basic anthropometrical characteristics associated to obesity were measured and the food intake was monitored using a 7-day record method. In the group of obese individuals, a subset of 34 morbidly obese patients was studied for plasma leptin and soluble leptin receptor levels. Results: None of the examined polymorphisms was associated to anthropometrical or demographic characteristics of the study subjects. The Gln223Arg polymorphism within the leptin receptor gene was significantly associated with lower plasma leptin levels (the RR genotype being more frequent in patients with lower plasma leptin levels; P = 0.001). No associations of the examined polymorphisms with food preferences was observed. Conclusions: Based on our results, the examined polymorphisms in the adipokine genes do not seem to be the major risk factor for obesity development in the Czech population nor significantly affect food preferences.

Extension of microRNA expression pattern associated with high-risk neuroblastoma

Clinical behavior of neuroblastoma (NBL) is remarkably heterogeneous, as it ranges from spontaneous regression to aggressive clinical phenotype and death. There is increasing body of evidence demonstrating that microRNAs could be considered the potential biomarkers for clinical applications in NBL. In this report, we focus on molecular characterization of high-risk as well as low-risk and intermediate-risk NBL cases in the context of the microRNA expression profile that is specific for the given risk category of the disease. We investigated a total of 30 NBL patients, out of whom there were 19 patients with low- to intermediate-risk and 11 with high-risk NBLs as defined by the Clinical Oncology Group. We determined the expression profiles of 754 microRNAs (miRNAs), whereas the miRNA expression levels were normalized to RNU44, mean expression levels were calculated, and data were analyzed by use of the microarray biostatistical approaches. We identified the signature of 38 miRNAs differentially expressed between these groups of NBL patients (P < 0.05): 17 miRNAs were upregulated and 21 miRNAs were downregulated in the tumors of high-risk NBL patients. We confirm some of the previous observations and we report several new microRNAs associated with aggressive NBL, both being relevant subjects for further translational validation and functional studies.