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1.
Wiklund ED Gao S Hulf T Sibbritt T Nair S Costea DE Villadsen SB Bakholdt V Bramsen JB Sørensen JA Krogdahl A Clark SJ Kjems J 《PloS one》2011,6(11):e27840
Background
MicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of >30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC.Methods
TaqMan® qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArray® mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44high oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers.Results
MiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44high oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids.Conclusions
MiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR-127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression. 相似文献2.
Miriam Ragle Aure Suvi-Katri Leivonen Thomas Fleischer Qian Zhu Jens Overgaard Jan Alsner Trine Tramm Riku Louhimo Grethe I Grenaker Aln?s Merja Per?l? Florence Busato Nizar Touleimat J?rg Tost Anne-Lise B?rresen-Dale Sampsa Hautaniemi Olga G Troyanskaya Ole Christian Lingj?rde Kristine Kleivi Sahlberg Vessela N Kristensen 《Genome biology》2013,14(11):R126
Background
The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide DNA methylation, copy number and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer.Results
We identify 70 miRNAs whose expression was associated with alterations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein.Conclusions
Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number alterations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer. 相似文献3.
Piepoli A Tavano F Copetti M Mazza T Palumbo O Panza A di Mola FF Pazienza V Mazzoccoli G Biscaglia G Gentile A Mastrodonato N Carella M Pellegrini F di Sebastiano P Andriulli A 《PloS one》2012,7(3):e33663
Background and Aim
Altered expression of microRNAs (miRNAs) hallmarks many cancer types. The study of the associations of miRNA expression profile and cancer phenotype could help identify the links between deregulation of miRNA expression and oncogenic pathways.Methods
Expression profiling of 866 human miRNAs in 19 colorectal and 17 pancreatic cancers and in matched adjacent normal tissues was investigated. Classical paired t-test and random forest analyses were applied to identify miRNAs associated with tissue-specific tumors. Network analysis based on a computational approach to mine associations between cancer types and miRNAs was performed.Results
The merge between the two statistical methods used to intersect the miRNAs differentially expressed in colon and pancreatic cancers allowed the identification of cancer-specific miRNA alterations. By miRNA-network analysis, tissue-specific patterns of miRNA deregulation were traced: the driving miRNAs were miR-195, miR-1280, miR-140-3p and miR-1246 in colorectal tumors, and miR-103, miR-23a and miR-15b in pancreatic cancers.Conclusion
MiRNA expression profiles may identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of tissue specific cancers. miRNA-network analysis help identify altered miRNA regulatory networks that could play a role in tumor pathogenesis. 相似文献4.
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Ribeiro-dos-Santos  Khayat AS Silva A Alencar DO Lobato J Luz L Pinheiro DG Varuzza L Assumpção M Assumpção P Santos S Zanette DL Silva WA Burbano R Darnet S 《PloS one》2010,5(10):e13205
Background
While microRNAs (miRNAs) play important roles in tissue differentiation and in maintaining basal physiology, little is known about the miRNA expression levels in stomach tissue. Alterations in the miRNA profile can lead to cell deregulation, which can induce neoplasia.Methodology/Principal Findings
A small RNA library of stomach tissue was sequenced using high-throughput SOLiD sequencing technology. We obtained 261,274 quality reads with perfect matches to the human miRnome, and 42% of known miRNAs were identified. Digital Gene Expression profiling (DGE) was performed based on read abundance and showed that fifteen miRNAs were highly expressed in gastric tissue. Subsequently, the expression of these miRNAs was validated in 10 healthy individuals by RT-PCR showed a significant correlation of 83.97% (P<0.05). Six miRNAs showed a low variable pattern of expression (miR-29b, miR-29c, miR-19b, miR-31, miR-148a, miR-451) and could be considered part of the expression pattern of the healthy gastric tissue.Conclusions/Significance
This study aimed to validate normal miRNA profiles of human gastric tissue to establish a reference profile for healthy individuals. Determining the regulatory processes acting in the stomach will be important in the fight against gastric cancer, which is the second-leading cause of cancer mortality worldwide. 相似文献7.
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Angela Schoolmeesters Teresa Eklund Devin Leake Annaleen Vermeulen Queta Smith Shelley Force Aldred Yuriy Fedorov 《PloS one》2009,4(5)
Background
Mesenchymal stem (MS) cells are excellent candidates for cell-based therapeutic strategies to regenerate injured tissue. Although human MS cells can be isolated from bone marrow and directed to differentiate by means of an osteogenic pathway, the regulation of cell-fate determination is not well understood. Recent reports identify critical roles for microRNAs (miRNAs), regulators of gene expression either by inhibiting the translation or by stimulating the degradation of target mRNAs.Methodology/Principal Findings
In this study, we employed a library of miRNA inhibitors to evaluate the role of miRNAs in early osteogenic differentiation of human MS cells. We discovered that miR-148b, -27a and -489 are essential for the regulation of osteogenesis: miR-27a and miR-489 down-regulate while miR-148b up-regulates differentiation. Modulation of these miRNAs induced osteogenesis in the absence of other external differentiation cues and restored osteogenic potential in high passage number human MS cells.Conclusions/Significance
Overall, we have demonstrated the utility of the functional profiling strategy for unraveling complex miRNA pathways. Our findings indicate that miRNAs regulate early osteogenic differentiation in human MS cells: miR-148b, -27a, and -489 were found to play a critical role in osteogenesis. 相似文献11.
Background
MicroRNAs (miRNAs) are reportedly involved in pancreatic ductal adenocarcinoma (PDAC) development. Current methods do not allow us to reliably monitor miRNA function. Asensors are adeno-associated virus (AAV) vector miRNA sensors for real-time consecutive functional monitoring of miRNA profiling in living cells.Methods
miR-200a, -200b, -21, -96, -146a, -10a, -155, and -221 in three PDAC cell lines (BxPC-3, CFPAC-1, SW1990), pancreatic epithelioid carcinoma cells (PANC-1), and human pancreatic nestin-expressing cells (hTERT-HPNE) were monitored by Asensors. Subsequently, the real-time consecutive functional profile of all miRNAs was evaluated.Results
Selected miRNAs were detectable in all cell lines with high sensitivity and reproducibility. In the three PDAC cell lines, BxPC-3, CFPAC-1, and SW1990, the calibrated signal unit of the eight miRNAs Asensors was significantly lower than that of the Asensor control. However, in PANC-1 cells, miR-200a and -155 showed upregulation of target gene expression at 24 hours after infection with the sensors; at 48 hours, miR-200b and -155 displayed upregulation of reporter expression; and at 72 hours, reporter gene expression was upregulated by miR-200a and -200b. The result that miRNA could upregulate gene expression was further confirmed in miR-155 of hTERT-HPNE cells. Furthermore, miRNA activity varied among cell/tissue types and time.Conclusion
It is possible that miRNA participates in the pathophysiology of pancreatic cancer, but the current popular methods do not accurately reveal the real-time miRNA function. Thus, this report provided a convenient, accurate, and sensitive approach to miRNA research. 相似文献12.
Introduction
A prerequisite to accurate interpretation of RQ-PCR data is robust data normalization. A commonly used method is to compare the cycle threshold (CT) of target miRNAs with those of a stably expressed endogenous (EC) miRNA(s) from the same sample. Despite the large number of studies reporting miRNA expression patterns, comparatively few appropriate ECs have been reported thus far. The purpose of this study was to identify stably expressed miRNAs with which to normalize RQ-PCR data derived from human blood specimens.Methods
MiRNA profiling of approximately 380 miRNAs was performed on RNA derived from blood specimens from 10 women with breast cancer and 10 matched controls. Analysis of mean expression values across the dataset (GME) identified stably expressed candidates. Additional candidates were selected from the literature and analyzed by the geNorm algorithm. Further validation of three candidate ECs by RQ-PCR was performed in a larger cohort (n = 40 cancer, n = 20 control) was performed, including analysis by geNorm and NormFinder algorithms.Results
Microarray screening identified 10 candidate ECs with expression patterns closest to the global mean. Geometric averaging of candidate ECs from the literature using geNorm identified miR-425 as the most stably expressed miRNA. MiR-425 and miR-16 were the best combination, achieving the lowest V-value of 0.185. Further validation by RQ-PCR confirmed that miR-16 and miR-425 were the most stably expressed ECs overall. Their combined use to normalize expression data enabled the detection of altered target miRNA expression that reliably differentiated between cancers and controls in human blood specimens.Conclusion
This study identified that the combined use of 2 miRNAs, (miR-16 and miR-425) to normalize RQ-PCR data generated more reliable results than using either miRNA alone, or use of U6. Further investigation into suitable ECs for use in miRNA RQ-PCR studies is warranted. 相似文献13.
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Hua Zhang Xue-Qun Luo Peng Zhang Li-Bin Huang Yu-Sheng Zheng Jun Wu Hui Zhou Liang-Hu Qu Ling Xu Yue-Qin Chen 《PloS one》2009,4(11)
Background
Recent reports have indicated that microRNAs (miRNAs) play a critical role in malignancies, and regulations in the progress of adult leukemia. The role of miRNAs in pediatric leukemia still needs to be established. The purpose of this study was to investigate the aberrantly expressed miRNAs in pediatric acute leukemia and demonstrate miRNA patterns that are pediatric-specific and prognostic parameter-associated.Methodology/Principal Findings
A total of 111 pediatric bone marrow samples, including 99 patients and 12 normal donors, were enrolled in this study. Of those samples, 36 patients and 7 normal samples were used as a test cohort for the evaluation of miRNA profiling; 63 pediatric patients and 5 normal donors were used as a validation cohort to confirm the miRNA differential expression. Pediatric ALL- and AML-specific microRNA expression patterns were identified in this study. The most highly expressed miRNAs in pediatric ALL were miR-34a, miR-128a, miR-128b, and miR-146a, while the highly expressed miRNAs in pediatric AML were miR-100, miR-125b, miR-335, miR-146a, and miR-99a, which are significantly different from those reported for adult CLL and AML. miR-125b and miR-126 may serve as favorable prognosticators for M3 and M2 patients, respectively. Importantly, we identified a “miRNA cascade” associated with central nervous system (CNS) relapse in ALL. Additionally, miRNA patterns associated with prednisone response, specific risk group, and relapse of ALL were also identified.Conclusions/Significance
There are existing pediatric-associated and prognostic parameter-associated miRNAs that are independent of cell lineage and could provide therapeutic direction for individual risk-adapted therapy for pediatric leukemia patients. 相似文献15.
Joshua C Kwekel Vikrant Vijay Varsha G Desai Carrie L Moland James C Fuscoe 《Biology of sex differences》2015,6(1)
Background
Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. MiRNAs in particular have been shown to be important regulators in cancer and other diseases and show promise as predictive biomarkers for diagnosis and prognosis. In this study, we characterized the global kidney miRNA expression profile in untreated male and female F344 rats throughout the life span. These findings were correlated with sex-specific susceptibilities to adverse renal events, such as male-biased renal fibrosis and inflammation in old age.Methods
Kidney miRNA expression was examined in F344 rats at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age in both sexes using Agilent miRNA microarrays. Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively. Pathway analysis software was used to investigate the possible roles of these target genes in age- and sex-specific differences.Results
Three hundred eleven miRNAs were found to be expressed in at least one age and sex. Filtering criteria revealed 174 differentially expressed miRNAs in the kidney; 173 and 34 miRNAs exhibiting age and sex effects, respectively. Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages. No significant sexually dimorphic miRNA expression was observed from 5 to 8 weeks, while the most differential expression (13 miRNAs) was observed at 21 weeks. Potential target genes of these differentially expressed miRNAs were identified.Conclusions
The expression of 56% of detected renal miRNAs was found to vary significantly with age and/or sex during the life span of F344 rats. Pathway analysis suggested that 2-week-expressed miRNAs may be related to organ and cellular development and proliferation pathways. Male-biased miRNA expression at older ages correlated with male-biased renal fibrosis and mononuclear cell infiltration. These miRNAs showed high representation in renal inflammation and nephritis pathways, and included miR-214, miR-130b, miR-150, miR-223, miR-142-5p, miR-185, and miR-296*. Analysis of kidney miRNA expression throughout the rat life span will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.Electronic supplementary material
The online version of this article (doi:10.1186/s13293-014-0019-1) contains supplementary material, which is available to authorized users. 相似文献16.
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Holly Rutledge Jeanette Baran-Gale Fernando Pardo-Manuel de Villena Elissa J. Chesler Gary A. Churchill Praveen Sethupathy Samir N. P. Kelada 《BMC genomics》2015,16(1)
Background
Allergic airway diseases (AADs) such as asthma are characterized in part by granulocytic airway inflammation. The gene regulatory networks that govern granulocyte recruitment are poorly understood, but evidence is accruing that microRNAs (miRNAs) play an important role. To identify miRNAs that may underlie AADs, we used two complementary approaches that leveraged the genotypic and phenotypic diversity of the Collaborative Cross (CC) mouse population. In the first approach, we sought to identify miRNA expression quantitative trait loci (eQTL) that overlap QTL for AAD-related phenotypes. Specifically, CC founder strains and incipient lines of the CC were sensitized and challenged with house dust mite allergen followed by measurement of granulocyte recruitment to the lung. Total lung RNA was isolated and miRNA was measured using arrays for CC founders and qRT-PCR for incipient CC lines.Results
Among CC founders, 92 miRNAs were differentially expressed. We measured the expression of 40 of the most highly expressed of these 92 miRNAs in the incipient lines of the CC and identified 18 eQTL corresponding to 14 different miRNAs. Surprisingly, half of these eQTL were distal to the corresponding miRNAs, and even on different chromosomes. One of the largest-effect local miRNA eQTL was for miR-342-3p, for which we identified putative causal variants by bioinformatic analysis of the effects of single nucleotide polymorphisms on RNA structure. None of the miRNA eQTL co-localized with QTL for eosinophil or neutrophil recruitment. In the second approach, we constructed putative miRNA/mRNA regulatory networks and identified three miRNAs (miR-497, miR-351 and miR-31) as candidate master regulators of genes associated with neutrophil recruitment. Analysis of a dataset from human keratinocytes transfected with a miR-31 inhibitor revealed two target genes in common with miR-31 targets correlated with neutrophils, namely Oxsr1 and Nsf.Conclusions
miRNA expression in the allergically inflamed murine lung is regulated by genetic loci that are smaller in effect size compared to mRNA eQTL and often act in trans. Thus our results indicate that the genetic architecture of miRNA expression is different from mRNA expression. We identified three miRNAs, miR-497, miR-351 and miR-31, that are candidate master regulators of genes associated with neutrophil recruitment. Because miR-31 is expressed in airway epithelia and is predicted to target genes with known links to neutrophilic inflammation, we suggest that miR-31 is a potentially novel regulator of airway inflammation.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1732-9) contains supplementary material, which is available to authorized users. 相似文献18.
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Background
As playing important roles in gene regulation, microRNAs (miRNAs) are believed as indispensable involvers in the pathogenesis of myocardial infarction (MI) that causes significant morbidity and mortality. Working on a hypothesis that modulation of only some key members in the miRNA superfamily could benefit ischemic heart, we proposed a microarray based network biology approach to identify them with the recognized clinical effect of propranolol as a prompt.Methods
A long-term MI model of rat was established in this study. The microarray technology was applied to determine the global miRNA expression change intervened by propranolol. Multiple network analyses were sequentially applied to evaluate the regulatory capacity, efficiency and emphasis of the miRNAs which dysexpression in MI were significantly reversed by propranolol.Results
Microarray data analysis indicated that long-term propranolol administration caused 18 of the 31 dysregulated miRNAs in MI undergoing reversed expression, implying that intentional modulation of miRNA expression might show favorable effects for ischemic heart. Our network analysis identified that, among these miRNAs, the prime players in MI were miR-1, miR-29b and miR-98. Further finding revealed that miR-1 focused on regulation of myocyte growth, yet miR-29b and miR-98 stressed on fibrosis and inflammation, respectively.Conclusion
Our study illustrates how a combination of microarray technology and functional protein network analysis can be used to identify disease-related key miRNAs. 相似文献20.
Teshome Tilahun Bizuayehu Steinar D Johansen Velmurugu Puvanendran Hilde Toften Igor Babiak 《BMC genomics》2015,16(1)