An evaluation and replication of miRNAs with disease stage and colorectal cancer-specific mortality
TL;DR: The findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.
Abstract: MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population-based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa-miR-145-5p and hsa-miR-31-5p showed increased expression with more advanced tumor stage, while hsa-miR-200b-3p, hsa-miR-215 and hsa-miR-451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa-miR-145-3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa-miR-9-3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa-miR-335-5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa-miR-374a-5p, hsa-miR-570-3p and hsa-miR-18a-5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.
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TL;DR: It is shown that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC) and was identified as a sponge of miR-145 and up-regulatedMiRNAs functional targets E2F5, BAG4 and FMNL2.
Abstract: // Huijun Xie 1, 2, 3, * , Xiaoli Ren 1, 2, 3, * , Sainan Xin 1, 2, 3, * , Xiaoliang Lan 4 , Guifeng Lu 1, 2, 3 , Yuan Lin 1, 2, 3 , Shaoshan Yang 1, 2, 3 , Zhicheng Zeng 1, 2, 3 , Wenting Liao 1, 2, 3 , Yan-Qing Ding 1, 2, 3 , Li Liang 1, 2, 3 1 Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China 2 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China 3 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China 4 Department of General Surgery, Nanfang Hospital, Guangzhou, Guangdong, China * These authors contributed equally to this work Correspondence to: Li Liang, email: redsnow007@hotmail.com Yan-Qing Ding, email: dyq@fimmu.com Keywords: hsa_circ_001569, miR-145, colorectal cancer, FMNL2, BAG4 Received: December 08, 2015 Accepted: March 07, 2016 Published: April 05, 2016 ABSTRACT Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.
371 citations
Cites background from "An evaluation and replication of mi..."
...MiR-145 is also closely related with the development of colon cancer [19, 20]....
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...MiR-145 has been associated with patientʼs survival after diagnosis with CRC [18, 19]....
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TL;DR: HX antisense intergenic RNA (HOTAIR) is a recently discovered long non-coding RNA that plays critical role in gene regulation and chromatin dynamics, appears to be misregulated in a variety of cancers.
342 citations
Cites background from "An evaluation and replication of mi..."
...tumors [82], Laryngeal squamous cell cancer [108, 109], gall bladder cancers [68], nonfunctional pituitary adenoma [110], prostate cancer [111], cervical tumors [109, 112, 113], melanomas [114], gastric cancers [45, 115, 116], Ta/T1 bladder cancer [72] and endometrial tumors [44,...
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TL;DR: The roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRN as well as miRNA regulators in colorectal cancer are reviewed and their stability in patient-derived samples and ease of detection with standard and novel techniques are discussed.
Abstract: MicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present in the human genome, ∼250 miRNAs are reported to have changes in abundance or altered functions in colorectal cancer. Thousands of studies have documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their frequent participation in feedback loops, which probably serve to reinforce or magnify biological outcomes to manifest a particular cellular phenotype. Here, we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs (anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability in patient-derived samples and ease of detection with standard and novel techniques, we also discuss the potential use of miRNAs as biomarkers in the diagnosis of colorectal cancer and as prognostic indicators of this disease. MiRNAs also represent attractive candidates for targeted therapies because their function can be manipulated through the use of synthetic antagonists and miRNA mimics.
112 citations
Cites background from "An evaluation and replication of mi..."
...The TGF-β pathway, which is important for repressing cellular proliferation and cell cycle progression is also antagonized by several miRNAs, including miR-17/106, miR-135b, and miR-20a through effects on TGFBR2 and SMAD4....
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...The miR-17 oncomiR family and modulation of TGF-β signaling The human miR-17 family consists of eight miRNAs (miR-17, miR-18a/b, miR-20a/b, miR-93, and miR-106a/b), with three of these (miR-17, miR-18a, and miR-20a) transcribed from the miR-17-92 miRNA locus....
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...Alternatively, and perhaps unexpectedly, given that TGF-β generally enhances EMT (Oft et al., 1998; Lamouille et al., 2014), TGFBR2 may repress migration and invasion, as observed by Feng et al. (2012), although such a role remains to be functionally dissected....
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...MiR-20a promotes CRC cell line migration, invasion and the expression of EMTmarkers (Sokolova et al., 2015; Xu et al., 2015; Cheng et al., 2016)....
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...MiR-106a targets the TGF-β recteptor TGFBR2 and is highly expressed in metastatic CRC cell lines, and promotes cancer cell migration and invasion in vitro (Feng et al., 2012)....
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TL;DR: A novel DE detection method is developed based on NanoString nCounter data that considers a generalized linear model of the negative binomial family to characterize count data and allows for multifactor design and performs better than existing methods.
Abstract: The advanced medium-throughput NanoString nCounter technology has been increasingly used for mRNA or miRNA differential expression (DE) studies due to its advantages including direct measurement of molecule expression levels without amplification, digital readout and superior applicability to formalin fixed paraffin embedded samples. However, the analysis of nCounter data is hampered because most methods developed are based on t-tests, which do not fit the count data generated by the NanoString nCounter system. Furthermore, data normalization procedures of current methods are either not suitable for counts or not specific for NanoString nCounter data. We develop a novel DE detection method based on NanoString nCounter data. The method, named NanoStringDiff, considers a generalized linear model of the negative binomial family to characterize count data and allows for multifactor design. Data normalization is incorporated in the model framework through data normalization parameters, which are estimated from positive controls, negative controls and housekeeping genes embedded in the nCounter system. We propose an empirical Bayes shrinkage approach to estimate the dispersion parameter in the model and a likelihood ratio test to identify differentially expressed genes. Simulations and real data analysis demonstrate that the proposed method performs better than existing methods.
107 citations
Cites background from "An evaluation and replication of mi..."
...miR-374a-5p upregulation is associated with reduced risk of dying from colorectal cancer (17)....
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...The upregulation of miR-145-5p is associated with more advanced colorectal cancer stage (17) and invasive breast cancer (18)....
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TL;DR: It is determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival and is distinguished as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that mi R-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
Abstract: MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
87 citations
References
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TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
31,015 citations
TL;DR: A method that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements is described, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.
Abstract: Microarrays can measure the expression of thousands of genes to identify changes in expression between different biological states. Methods are needed to determine the significance of these changes while accounting for the enormous number of genes. We describe a method, Significance Analysis of Microarrays (SAM), that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements. For genes with scores greater than an adjustable threshold, SAM uses permutations of the repeated measurements to estimate the percentage of genes identified by chance, the false discovery rate (FDR). When the transcriptional response of human cells to ionizing radiation was measured by microarrays, SAM identified 34 genes that changed at least 1.5-fold with an estimated FDR of 12%, compared with FDRs of 60 and 84% by using conventional methods of analysis. Of the 34 genes, 19 were involved in cell cycle regulation and 3 in apoptosis. Surprisingly, four nucleotide excision repair genes were induced, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.
12,102 citations
TL;DR: Three methods of performing normalization at the probe intensity level are presented: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure and the simplest and quickest complete data method is found to perform favorably.
Abstract: Motivation: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. Results: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. Availabilty: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. Contact: bolstad@stat.berkeley.edu Supplementary information: Additional figures may be found at http://www.stat.berkeley.edu/∼bolstad/normalize/ index.html
8,324 citations
TL;DR: MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment and has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein-coding genes involved in cancer.
Abstract: MicroRNA (miRNA ) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein- coding genes involved in cancer.
6,345 citations
Journal Article•
TL;DR: The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery as discussed by the authors.
Abstract: MicroRNA (miRNA) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein- coding genes involved in cancer.
6,306 citations