miRNA Expression Profiling Studies Research Articles

Abstract TMP111: The Detrimental Effects Of Post-stroke Social Isolation On Microglial Activation Is Mediated By MicroRNAs

Introduction: Social Isolation (SI) is a risk factor for a wide array of psychological disorders. SI significantly enhances the incidence of developing neurological diseases, including stroke within the elderly population. Recent studies have shown microRNA (miRNA) signatures in the brain and the circulation are altered in social defeat models and under stressful environmental conditions. Although SI has shown to influence post-stroke recovery, potential targetable interventions to mitigate these inflammatory events are limited. Hypothesis: Post-stroke SI influences temporally distinct miRNA networks in the brain that regulate acute microglial activation and contribute to chronic depressive phenotypes. Methods: Aged (18-20 month) C57BL/6 male mice were subjected to 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion. Mice were randomly assigned to either continued pair housing (PH), or SI three days after a 60-minute MCAO. Mice were euthanized at post-stroke SI Day 1, 4, and 27 and ipsilateral hemispheres were collected for miRNA sequencing and downstream analysis. Behavioral tests and brain cell analysis using flow cytometry were performed using independent experimental cohorts. Results: The top 10 differentially expressed miRNAs were identified in SI vs. PH mice across three time points (FC ≥ 1.5, FDR adjusted P <0.05, n=4/group). Interactional network analysis revealed miR-466i-3p, miR-10a-5p, and miR-10b-5p as pivotal nodes that regulated the expression of the largest subset of genes involved in microglial-specific immune activation and chronic depression after stroke at SI D4 and D27, respectively. Flow cytometry analysis showed that microglia are significantly activated at post-stroke SI Day 4, as assessed by the downregulation of microglia-specific homeostatic protein purinergic receptor P2RY12 ( P <0.05, n=7-8/group) and interestingly, chronic SI induced depressive-like behaviors in aged stroke mice; consistent with our miRNA-based pathway analysis. Conclusion: This is the first comprehensive miRNA expression profiling study using NGS technique in aging, stroke, and SI. Our data revealed that SI-specific miRNAs are involved in microglial activation and chronic depression in aged mice.

MicroRNA-Expression Profiling in Myopia: A Meta-Analysis and Systematic Review

Background: Myopia (nearsightedness) is currently the most common human eye disorder, worldwide. In the recent years, several studies have addressed the role of microRNAs (miRNAs) in the pathogenesis of myopia. Objectives: The aim of this study was to perform a meta-analysis on the miRNA-expression profiling studies in myopia to identify commonly dysregulated miRNAs in myopic tissues. Method: Seven independent studies were included in the meta-analysis. A vote-counting strategy was employed as the meta-analysis method. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) functional enrichment analysis were performed to identify the pathways most strongly affected by the dysregulated mouse miRNAs. Results: According to the vote-counting method, eighteen miRNAs were reported in at least 2 studies with the consistent direction, of which 13 miRNAs were commonly upregulated in myopic samples compared with control samples, and five miRNAs were commonly downregulated. Subgroup analyses divided and compared the differentially expressed miRNAs according to species (human and animal) and ocular tissue types. The KEGG analysis showed that the dysregulated mouse miRNAs were most enriched in extracellular matrix-receptor interaction signal pathway. The most enriched GO process regulated by the dysregulated mouse miRNAs was cellular protein modification process. Conclusions: Our meta-analysis recommends several miRNAs may provide some clues of the potential biomarkers in myopia. Further mechanistic studies are warranted to elucidate the biological role of the dysregulated miRNAs in the development of myopia.

Hsa-miR-374b-5p regulates expression of the gene U2AF homology motif (UHM) kinase 1.

We aimed to identify a microRNA (miRNA) that is significantly upregulated in blood and in cells of the oral mucosa upon exposure to the periodontitis main risk factors oral inflammation and tobacco smoke, to subsequently identify its target gene and to describe the molecular mechanism of gene regulation. miRNAs are associated with many disorders. Array-based miRNA expression studies indicated a number of differentially expressed miRNAs in the pathology of oral diseases. However, these miRNAs mostly lacked replication, and their target genes have remained unknown. 863 miRNAs were analyzed in blood from 18 PD cases and 70 controls (Geniom Biochip). Selected miRNAs were analyzed for upregulation in the inflamed oral mucosa of PD patients using published miRNA expression profiling studies from gingival cells. hsa-miR-374b-5p mimic was overexpressed in primary gingival fibroblasts (pGFs) from 3 donors, and genome-wide mRNA expression was quantified (Clarion Array). Gene-specific regulation was validated by qRT-PCR and Luciferase activity in HeLa cells. hsa-miR-374b-5p showed >twofold change (FC) in 3 independent studies performed in blood, gingival tissues, and cells. After hsa-miR-374b-5p overexpression, genome-wide expression analysis showed UHMK1 as top 1 downregulated gene in pGFs (p=2.5×10-04 , fold change=-1.8). Reporter genes demonstrated that hsa-miR-374b-5p downregulates mRNA levels (p=.02; FC=-1.5), leading to reduction in protein activity (p=.013, FC=-1.3). hsa-miR-374b-5p is upregulated in blood and ginvial cells exposed to oral inflammation and tobacco smoke and regulates UHMK1, which has a role in osteoclast differentiation.

Ultrasensitive electrochemical detection of miRNA coupling tetrahedral DNA modified gold nanoparticles tags and catalyzed hairpin assembly

MicroRNAs (miRNAs) play key regulatory roles in a number of biological processes, which act as critical biomarkers for clinical diagnosis. There are urgent needs to develop advanced tools for accurate and convenient analysis of miRNA in biological circumstances. In this study, an ultrasensitive electrochemical biosensor for miRNA assay is fabricated. Tetrahedral DNA modified gold nanoparticles tags are applied with optimized orientation, which are able to recruit a large number of electrochemical species for remarkable signal responses. Benefiting from the excellent amplification efficiency of the association of strand displacement amplification and catalyzed hairpin assembly, the established method shows ultrahigh sensitivity with the limit of detection as low as 10 aM. A wide linear range from 10−17 to 10−7 M is achieved. In addition, this method is capable to specifically discriminate interfering miRNAs with slightly different sequences. The successful assessment of miRNA levels in human serum samples also demonstrates good practical utility. Therefore, the proposed method has great potential to the applications of miRNA expression profiling and biological studies.

A meta-analysis of microRNA expression profiling studies in heart failure.

Heart failure (HF) is a major consequence of many cardiovascular diseases with high rate of morbidity and mortality. Early diagnosis and prevention are hampered by the lack of informative biomarkers. The aim of this study was to perform a meta-analysis of the miRNA expression profiling studies in HF to identify novel candidate biomarkers or/and therapeutic targets. A comprehensive literature search of the PubMed for miRNA expression studies related to HF was carried out. The vote counting and robust rank aggregation meta-analysis methods were used to identify significant meta-signatures of HF-miRs. The targets of HF-miRs were identified, and network construction and gene set enrichment analysis (GSEA) were performed to identify the genes and cognitive pathways most affected by the dysregulation of the miRNAs. The literature search identified forty-five miRNA expression studies related to CHF. Shared meta-signature was identified for 3 up-regulated (miR-21, miR-214, and miR-27b) and 13 down-regulated (miR-133a, miR-29a, miR-29b, miR-451, miR-185, miR-133b, miR-30e, miR-30b, miR-1, miR-150, miR-486, miR-149, and miR-16-5p) miRNAs. Network properties showed miR-29a, miR-21, miR-29b, miR-1, miR-16, miR-133a, and miR-133b have the most degree centrality. GESA identified functionally related sets of genes in signaling and community pathways in HF that are the targets of HF-miRs. The miRNA expression meta-analysis identified sixteen highly significant HF-miRs that are differentially expressed in HF. Further validation in large patient cohorts is required to confirm the significance of these miRs as HF biomarkers and therapeutic targets.

Acrylamide alters the miRNA profiles and miR‐27a‐5p plays the key role in multiple tissues of rats

AbstractAcrylamide (AA) is the potential carcinogen, which can induce multiple toxic effects in laboratory animals and humans. So far, increasing attention have been paid to toxical mechanism and intervention measures of AA, however, these details and methods are still obscure. MicroRNAs (miRNAs) have been demonstrated to be involved in toxical functional mechanisms induced by chemicals in vivo or vitro. To explore novel target and mechanism of AA toxicity, a more detailed miRNA expression profiling study is needed. In this study, we established the short‐term high‐dose model of rats with the treatment of 35 mg/kg·b.w./day AA for 17 days, analyzed the miRNAs expression profiling in AA and control groups, and discovered the altered miRNA profiles in 11 tissues with AA treatment. Interestingly enough, the expression of miR‐27a‐5p were significantly up‐regulated in AA group, especially in bladder and hepar. Furthermore, we found miR‐27a‐5p increased in 11 tissues of long‐term low‐dose AA‐treated rats (3.5 mg/kg·b.w./day for 68 days). Therefore, these results revealed that AA changed miRNAs profiles in multiple tissues of SD rats for the first time and suggested that miR‐27a‐5p could be used as the target biomarker for the detection and interference of AA toxicity.

MicroRNA Expression Profiling Based on Microarray Approach in Human Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Diabetes mellitus (DM) is one of the growing public health threats globally and as one of the common serious microvascular complications of DM, diabetic retinopathy (DR) is the leading cause of irreversible visual impairments and blindness. There is growing concern about the role of microRNAs (miRNAs) in the pathogenesis of DR. This meta-analysis was designed to collect those published miRNA expression profiling studies that compared the miRNA expression profiles in the biological samples of DR patients with those in the control group. Eight publications were finally included in the meta-analysis, and a total of 93 differentially expressed miRNAs were reported. Although six miRNAs were reported in at least two studies and with the consistent direction, after stratification by the type of biological samples, miR-320a was consistently reported to be upregulated in two serum sample-based studies and miR-423-5p was consistently reported to be upregulated in two vitreous humor sample-based studies. miR-27b was consistently reported to be downregulated in two serum sample-based studies. In conclusion, the results of this meta-analysis of human DR miRNAs' expression profiling studies might provide some clues of the potential biomarkers of DR. Further investigation of the mechanisms of miRNAs and more external validation studies are warranted with the aim of developing new diagnostic markers for preventing or reversing DR.

In silico analysis of miRNA role in resistance of hepatocellular carcinoma Bel-7402 cells to TRAIL

Context: To this date, the exact basics of microRNAs (miRNAs) mechanisms in inducing a resistance to tumor necrosis factor –related apoptosis-inducing ligand (TRAIL) signaling pathways remain unclear. Aims: The aim of this study was to analyze miRNA signaling pathways in TRAIL-resistant Bel-7402 cell line. Materials and Methods: The Gene Expression Omnibus (GEO) database was studied for miRNA expression profiling studies in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. By searching through databases of DIANAmT, miRanda, miRDB, miRWalk, and PICTAR using the online tools of miRWalk and TargetScan, target genes of miRNAs were predicted to express differentially by up to 50% in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Afterwards, signaling pathways and biological functions of miRNA target genes in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells were analyzed by the DAVID database. Results: A total of 352 miRNAs (186 up- and 166 downregulated miRNAs) were obtained from GSE74130 GEO DataSets accession item. The upregulated miRNAs including hsa-mir-145, hsa-mir-188, hsa-mir-221, hsa-mir-4802-5p, hsa-mir-198, hsa-mir-1184, and hsa-mir-345-3p were significantly intensified in apoptotic signaling pathway and process. The downregulated miRNAs including hsa-mir-138, hsa-mir-375, hsa-mir-449, hsa-mir-637, hsa-mir-208-3p, hsa-mir-4783-5p, hsa-mir-548b-3p, hsa-mir-127-3p, hsa-mir-92b-5p, hsa-mir-375, hsa-mir-503-5p, hsa-mir-499a-3p, and hsa-mir-154-3p were significantly raised in expression in cancer stem cell pathways. Conclusions: Analysis of miRNA expression profile revealed that some of the upregulated miRNAs negatively contributed to the regulation of apoptosis signaling pathways and cell cycle arrest as well as promoting TRAIL-induced apoptosis resistance in TRAIL-resistant Bel-7402 cells. Also, down-regulated miRNAs were probably involved in cancer stem cell processing.

Identification and validation of microRNAs and their targets expressed in osteosarcoma

Osteosarcoma (OS) is the most common type of bone cancer in children and adolescents, and has a poor prognosis. Previous studies have demonstrated that a number of microRNAs (miRNAs) were deregulated in OS, and that the expression of certain miRNAs was correlated with the stage of OS. Therefore, miRNAs may serve a role as a diagnostic and prognostic biomarker of OS. miRNA and mRNA integrated analysis of public expression profiles in the Gene Expression Omnibus database for OS was performed, and the regulated targets of miRNA in OS were predicted. Next, the regulatory network of miRNAs/genes was constructed and verified by reverse transcription-quantitative polymerase chain reaction in tissues and MG-63 cell lines. Two miRNA expression profiling studies and four eligible mRNA expression profiling studies were selected. Ten upregulated miRNAs, 5 downregulated miRNAs and 5 DGEs were identified in OS compared with normal tissues. hsa-miR-346 was inversely correlated with the target gene c-FLIP, which was consistent with the results of integrated analysis. In vitro, pre-miRNA-346 can downregulate the protein expression of c-FLIP, while not changing the mRNA level of c-FLIP. In the regulatory network, hsa-miR-346 and its target gene, c-FLIP, can be used as biomarkers for an earlier diagnosis of OS.

MicroRNA signature predicts survival in papillary thyroid carcinoma.

Papillary thyroid cancer (PTC) accounts for the majority of malignant thyroid tumors. Recently, several microRNA (miRNA) expression profiling studies have used bioinformatics to suggest miRNA signatures as potential prognostic biomarkers in various malignancies. However, a prognostic miRNA biomarker has not yet been established for PTC. The aim of the present study was to identify miRNAs with prognostic value for the overall survival (OS) of patients with PTC by analyzing high-throughput miRNA data and their associated clinical characteristics downloaded from The Cancer Genome Atlas database. From our dataset, 150 differentially expressed miRNAs were identified between tumor and nontumor samples; of these miRNAs, 118 were upregulated and 32 were downregulated. Among the 150 differentially expressed miRNAs, a four miRNA signature was identified that reliably predicts OS in patients with PTC. This miRNA signature was able to classify patients into a high-risk group and a low-risk group with a significant difference in OS (P < .01). The prognostic value of the signature was validated in a testing set ( P < .01). The four miRNA signature was an independent prognostic predictor according to the multivariate analysis and demonstrated good performance in predicting 5-year disease survival with an area under the receiver operating characteristic curve area under the curve (AUC) score of 0.886. Thus, this signature may serve as a novel biomarker for predicting the survival of patients with PTC.

New mechanistic insights of clear cell renal cell carcinoma from integrated miRNA and mRNA expression profiling studies

Differentially expressed (DE) microRNAs (miRNAs) in clear cell renal cell carcinoma (ccRCC) tissues from pooled samples were reported to affect the tumorigenesis and progression of ccRCC. However, systematic studies on the miRNA-mRNA regulatory networks involved in various pathways in all four stages of the disease are lacking. In this study, we applied microarray technology to perform an integrated analysis of the miRNome and transcriptome in ccRCC tissues from patients at different stages of ccRCC. A total of 604 DEmiRNAs and 6892 DEgenes (DEGs) were identified by comparison with corresponding adjacent normal tissues. The pairing of miRNAs with DEGs were searched using validated miRWalk module, and the pairs were confirmed by comparing with DEmiRNAs in our study. Our results demonstrated that different stages of ccRCC had distinct miRNA/mRNA profiles. However, four common pathways (the complement and coagulation cascades, the pathway for the metabolism of xenobiotics by cytochrome P450, the PPAR signaling pathway, and the pathway for aldosterone-regulated sodium reabsorption) were enriched by targets of DEmiRNAs at all stages of ccRCC. We carried out an extensive analysis of data on miR-16, which had the most target genes, and found that its differential expression was validated in The Cancer Genome Atlas dataset. We also verified the correlation between miR-16 expression and target pathways by gene set enrichment analysis and in vitro experiments. High miR-16 level was also associated with shorter survival time in ccRCC. Our work presents a systematic profiling of miRNA, mRNA and pathways regulated by miRNAs in different stages of ccRCC. Our cross-omics results also identify four common pathways that function aberrantly in all stages of the disease. These pathways are likely to be critical in occurrence and progression of ccRCC. These common dysfunctional pathways have the potential to serve as therapeutic targets and diagnostic biomarkers, whereas miRNAs (miR-20, 484, 497) differentially expressed in only stage I tissues and in blood could be used to diagnose early-stage ccRCC patients.

Regulation of muscle atrophy by microRNAs: 'AtromiRs' as potential target in cachexia.

To provide an overview and describe the mode of action of miRNAs recently implicated in muscle atrophy, and discuss the challenges to explore their potential as putative therapeutic targets in cachexia. Recent work showed differentially expressed miRNAs in skeletal muscle of patients with cachexia-associated diseases. Studies using experimental models revealed miRNA regulation of the anabolic IGF-1 and catabolic TGF- β/myostatin pathways, and downstream protein synthesis and proteolysis signaling in control of muscle mass. Cachexia is a complex metabolic condition associated with progressive body weight loss, wasting of skeletal muscle mass and decrease in muscle strength. MiRNAs play a central role in post-transcriptional gene regulation by targeting mRNAs, thereby coordinating and fine-tuning many cellular processes. MiRNA expression profiling studies of muscle biopsies have revealed differentially expressed miRNAs in patients with low muscle mass or cachexia. Evaluation in experimental models has revealed muscle atrophy, inhibition of protein synthesis and activation of proteolysis in response to modulation of specific miRNAs, termed 'atromiRs' in this review. These exciting findings call for further studies aimed at exploring the conservation of differentially expressed miRNAs across diseases accompanied by cachexia, identification of miRNA clusters and targets involved in muscle atrophy, and probing whether these miRNAs might be potential therapeutic targets for cachexia.

Identification of candidate microRNA biomarkers in diabetic nephropathy: a meta-analysis of profiling studies.

The aim was to perform a meta-analysis on the miRNA expression profiling studies in diabetic nephropathy (DN) to identify candidate diagnostic biomarkers. A comprehensive literature search was done in several databases and 53 DN miRNA expression studies were selected. To identify significant DN-miR meta-signatures, two meta-analysis methods were employed: vote-counting strategy and the robust rank aggregation method. The targets of DN-miRs were obtained and a gene set enrichment analysis was carried out to identify the pathways most strongly affected by dysregulation of these miRNAs. We identified a significant miRNA meta-signature common to both meta-analysis approaches of three up-regulated (miR-21-5p, miR-146a-5p, miR-10a-5p) and two down-regulated (miR-25-3p and miR-26a-5p) miRNAs. Besides that, subgroup analyses divided and compared the differentially expressed miRNAs according to species (human and animal), types of diabetes (T1DN and T2DN) and tissue types (kidney, blood and urine). Enrichment analysis confirmed that DN-miRs supportively target functionally related genes in signaling and community pathways in DN. Five highly significant and consistently dysregulated miRNAs were identified, and future studies should focus on discovering their potential effect on DN and their clinical value as DN biomarkers and therapeutic mediators.

MicroRNA, an Antisense RNA, in Sensing Myeloid Malignancies.

Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are clonal diseases arising in hematopoietic stem or progenitor cells. In recent years, microRNA (miRNA) expression profiling studies have revealed close associations of miRNAs with cytogenetic and molecular subtypes of myeloid malignancies, as well as outcome and prognosis of patients. However, the roles of miRNA deregulation in the pathogenesis of myeloid malignancies and how they cooperate with protein-coding gene variants in pathological mechanisms leading to the diseases have not yet been fully understood. In this review, we focus on recent insights into the role of miRNAs in the development and progression of myeloid malignant diseases and discuss the prospect that miRNAs may serve as a potential therapeutic target for leukemia.

Integrating MicroRNA Expression Profiling Studies to Systematically Evaluate the Diagnostic Value of MicroRNAs in Pancreatic Cancer and Validate Their Prognostic Significance with the Cancer Genome Atlas Data

Background/Aims: MicroRNAs (miRNAs) are promising biomarkers for pancreatic cancer (PaCa). However, systemic and unified evaluations of the diagnostic value of miRNAs are lacking. Therefore, we performed a systematic evaluation based on miRNA expression profiling studies. Methods: We obtained miRNA expression profiling studies from Gene Expression Omnibus (GEO) and ArrayExpress (AE) databases and calculated the pooled sensitivity, specificity, and summary area under a receiver operating characteristic (ROC) curve for every miRNA. According to the area under the curve (AUC), we identified the miRNAs with diagnostic potentiality and validated their prognostic role in The Cancer Genome Atlas (TCGA) data. Gene Ontology (GO) annotations and pathway enrichments of the target genes of the miRNAs were evaluated using bioinformatics tools. Results: Ten miRNA expression profiling studies including 958 patients were used in this diagnostic meta-analysis. A total of 693 miRNAs were measured in more than 9 studies. The top 50 miRNAs with high predictive values for PaCa were identified. Among them, miR-130b had the best predictive value for PaCa (pooled sensitivity: 0.73 [95% confidence intervals (CI) 0.44-0.91], specificity: 0.81 [95% CI 0.59–0.93], and AUC: 0.84 [95% CI 0.73–0.95]). We identified nine miRNAs (miR-23a, miR-30a, miR-125a, miR-129-1, miR-181b-1, miR-203, miR-221, miR-222, and miR-1301) associated with overall survival in PaCa patients by combining our results with TCGA data. The results of a Cox model revealed that two miRNAs (miR-30a [hazard ratio (HR)=2.43, 95% CI 1.05-5.59; p=0.037] and miR-203 [HR=3.14, 95% CI 1.28-7.71; p=0.012]) were independent risk factors for prognosis in PaCa patients. In total, 405 target genes of the nine miRNAs were enriched with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and cancer-associated pathways such as Ras signaling pathways, phospholipase D signaling pathway, and AMP-activated protein kinase (AMPK) signaling pathway were revealed among the top 20 enriched pathways. There were significant negative correlations between miR-181b-1 and miR-125a expression levels and the methylation status of their promoter region. Conclusion: Our study performed a systematic evaluation of the diagnostic value of miRNAs based on miRNA expression profiling studies. We identified that miR-23a, miR-30a, miR-125a, miR-129-1, miR-181b-1, miR-203, miR-221, miR-222, and miR-1301 had moderate diagnostic value for PaCa and predicted overall survival in PaCa patients.

MicroRNA Expression Analysis: Next-Generation Sequencing.

MicroRNAs are a class of small noncoding RNAs that function as regulators involving in many biological processes. The evaluation of miRNAs and their targets has been aided by miRNA expression profiling studies including multiplex PCR, microarrays, and recent next-generation sequencing tools. Next-generation sequencing has enabled us to profile thousands of genes in a single experiment and overcome the background signal and cross-hybridization issues of microarrays. Next-generation sequencing also allows for the simultaneous confirmation of known miRNAs and discovery of new miRNAs, and significantly reduces costs while providing billions of nucleotide information within a single experiment. Here we describe a detailed procedure of generation of miRNA library for next-generation sequencing to increase the efficiency of adapter ligation and finally construct a more specific cDNA library for sequencing and analyses for miRNA expression profiling.

Computational identification of microRNAs and their targets in liver cirrhosis.

Previous studies have revealed that the deregulation of circulating miRNAs is associated with liver cirrhosis. The present study aimed to identify reliable candidate biomarkers to improve the early detection of liver cirrhosis. An integrated analysis of expression profiles of microRNAs (miRNAs/miRs) and mRNAs in liver cirrhosis tissues from the GEO database was performed. Next, the regulatory targets of the differentially expressed miRNAs in liver cirrhosis tissues were predicted. In addition, a regulatory network of miRNA-target genes was constructed. A total of 4 eligible mRNA expression profiling studies and 2 miRNA expression profiling studies met the inclusion criteria, and were thus included. A total of 48 differentially expressed miRNAs and 1,773 differentially expressed genes were identified in liver cirrhosis tissues compared with normal tissues. There were 240 miRNA-target pairs whose expression was negatively correlated. In the miRNA-target regulatory network, overexpression of miR-21 and miR-199a-3p was suggested to be closely associated with the progression of liver cirrhosis. In addition, functional enrichment analysis of the target genes indicated that cell cycle was the most significantly enriched pathway, and the dysregulation of leukemia inhibitory factor, cancerous inhibitor of protein phosphatase 2A and retinoblastoma-associated protein 1 clearly suggested their importance in the development of liver cirrhosis. We hypothesized that miR-21 and miR-199a-3p may be promising non-invasive diagnostic biomarkers for the early diagnosis of liver cirrhosis. The miRNA-target regulatory network may provide additional insight into the current data regarding the role of miRNAs in liver cirrhosis.

Androgen receptor-mediated downregulation of microRNA-221 and -222 in castration-resistant prostate cancer.

MicroRNAs (miRNAs) play important roles in cancer formation and progression by suppressing the production of key functional proteins at the post-transcriptional level in a sequence-specific manner. While differential expression of miRNAs is widely observed in cancers including prostate cancer (PCa), how these miRNAs are transcriptionally regulated is largely unknown. MiRNA-221 and miRNA-222 (miR-221/-222) are well-established oncogenes and overexpressed in breast, liver, pancreas, and lung cancer, but their expression and biological functions in PCa remain controversial. Both up and down regulation have been observed in patient samples. Specifically, studies have demonstrated miR-221/-222 function as oncogenes, and promote PCa cell proliferation and the development of castration-resistant prostate cancer (CRPC). However, the expression level of miR-221/-222 is downregulated in several miRNA expression profiling studies. In this study, we demonstrate miR-221/-222 are androgen receptor (AR)-repressed genes and reside in a long primary transcript (pri-miRNA). Derepression of miR-221/-222 after androgen deprivation therapy (ADT) may enhance PCa cell proliferation potential through promoting G1/S phase transition. This function is likely transient but important in the development of CRPC. Downregulation of miR-221/-222 subsequently occurs once AR activity is restored through AR overexpression in CRPC. Our findings shed light on the complexity of transcriptional regulation of miRNAs in PCa and suggest context-dependent targeting of oncogenic miRNAs.

Abstract 2540: miR-196b as a potential biomarker for human esophageal cancer

Abstract Esophageal cancer is the sixth most common cause of cancer related death. Although multiple genetic and epigenetic alterations have been detected in esophageal cancer, molecular markers for early diagnosis and prediction of prognosis or treatment responses are quite limited. microRNA (miRNA) is a class of small-regulatory non-coding RNA, acting as either a tumor suppressor or oncogene by regulating gene expression through pairing with complementary seed of the targeted messenger RNAs (mRNA). A number of miRNA expression profiling studies have been conducted in esophageal. In our current study, we analyzed the most recent studies on miRNAs expression profiles in esophageal cancer. Consistently dysregulated miRNAs have been identified in esophageal cancer, including upregulation of miR-196b, miR-135a, and downregulation of miR-141, miR-200a-5p, miR-200b-3p, miR-27b, miR-210. We first assessed expression of miRNAs in esophageal cancer cell lines and primary esophageal cancer tissues by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Significantly overexpressed miR-196b was observed in human esophageal squamous cell carcinoma KYSE-70 and KYSE-180 compared with normal esophageal squamous cell line, HET-1A. Furthermore, overexpression of miR-196b was detected in 12 out of 14 (86%) cancer tissues compared to the matched normal tissues. Forced expression of miR-196b promotes the proliferation and invasion in esophageal cancer cell lines. TargetScanS and miRanda were used to identify the target genes of miR-196b. A list of targets genes were predicted, including GATA6, ARHGAP28, EPS15 and EPHA7. Forced expression of miR-196b resulted in significant downregulated EPS15 and EPHA7 expression in esophageal cancer cell lines. Our present work suggested that miR-196b acts as an oncomiR by regulating EPS15 and EPHA7. Therefore, miR-196b could be used as a biomarker for esophageal cancer. Citation Format: Xiaohui Tan, Tao Chen, Robert Siegel, Sidney Fu. miR-196b as a potential biomarker for human esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2540. doi:10.1158/1538-7445.AM2017-2540

A novel microRNA signature predicts survival in stomach adenocarcinoma.

Recent microRNA (miRNA) expression profiling studies suggest the clinical use of miRNAs as potential prognostic biomarkers in various malignancies. In this study, aiming to identify microRNAs with prognostic value for overall survival (OS) in stomach adenocarcinoma (STAD) patients, we analyzed the miRNA expression profiles and the associated clinical characteristics in 380 STAD samples from The Cancer Genome Atlas (TCGA) dataset. An eight-miRNA signature for predicting OS in STAD patients was identified and self-validated by survival analysis and semi-supervised principal components method. We developed a linear prognostic model composed of these miRNAs to divide patients into high- and low-risk groups according to the calculated prognostic scores. Kaplan-Meier analysis demonstrated that patients in the high-risk group had worse OS compared with patients in the low-risk group. Notably, this miRNA prognostic model showed prognostic significance to the STAD patients in early stages and the chemo-resistant patients, who would potentially benefit from additional medical interventions. Finally, this eight-miRNA signature is an independent prognostic biomarker and demonstrates a good predictive performance for 5-year survival. Thus, this signature may serve as a novel biomarker for predicting survival as well as chemotherapy response in STAD patients.