Dataset Information

Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance.

ABSTRACT: microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079-2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057-1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC.

SUBMITTER: Shi KQ

PROVIDER: S-EPMC4694817 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance.

Shi Ke-Qing KQ Lin Zhuo Z Chen Xiang-Jian XJ Song Mei M Wang Yu-Qun YQ Cai Yi-Jing YJ Yang Nai-Bing NB Zheng Ming-Hua MH Dong Jin-Zhong JZ Zhang Lei L Chen Yong-Ping YP

Oncotarget 20150901 28

microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Gen ...[more]

PMID: 26231037

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Project description:BackgroundGastric cancer (GC) is one of the common gastrointestinal malignancy worldwide and exhibits a poor prognosis. Increasing studies have indicated that microRNAs play critical roles in the cancer progression and have shown great potential as useful biomarkers. The search for potential diagnostic and prognostic biomarkers of gastric cancer (GC) with integrated bioinformatics analyses has been undertaken in previous studies.MethodsIn this study, the robust rank aggregation (RRA) method was used to perform an integrated analysis of differentially expressed miRNAs (DEMs) from five microarray datasets in the Gene Expression Omnibus (GEO) database to find robust biomarkers for GC. Ultimately, seven miRNAs were filtered from fourteen primary miRNAs using the validation set of The Cancer Genome Atlas (TCGA) database. Based on these results, diagnostic and survival analyses were performed, and logistic regression and Cox regression were used to determine the clinicopathological characteristics of the DEM expression and overall survival.ResultsNine eligible miRNA datasets related to GC were selected from the GEO database for integrated analysis in this study. Diagnostic analysis implied that these miRNAs could be regarded as promising candidate diagnostic biomarkers in GC tissues, but whether the results of the tissue analysis are consistent with those of peripheral blood analysis requires further validation. The logistic regression indicated that the ectopic expression of these DEMs was relevant to the histological type, anatomical region, and pathological grade of GC. However, the survival and Cox regression analyses suggested that the poor prognosis of GC patients was not strongly dependent on the ectopic expression of the seven miRNAs, but rather, a poor prognosis was associated with age, metastasis, and histological grade.ConclusionsBased on the results presented in this study it can be concluded that these miRNAs (miR-455-3p, miR-135b-5p, let-7a-3p, miR-195-5p, miR-204-5p, miR-149-5p, and miR-143-3p) might be potential biomarkers for the early diagnosis of GC patients, but this finding should be regarded with caution. A large-scale, prospective, and multicenter cohort study should be performed.

Project description:Background:Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors. The prognosis of HCC patients is still unsatisfying. Thus, it is of great importance to identify novel molecules and functional pathways associated with the pathophysiology of HCC. In this study, we performed the integrated bioinformatics analysis and experiment validation to identify novel biomarkers in the prognosis and progression of HCC. Materials and Methods:Gene expression profiles were obtained from Gene Expression Omnibus database (GSE33294) for the screening of the differentially expressed genes (DEGs) between HCC tissues and matched non-tumor tissues. The DEGs were subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Set Enrichment Analysis (GSEA). The key genes in HCC were further subjected to overall survival analysis of HCC patients. The in vitro functional studies were performed to validate the biological functions of the key gene in HCC cell progression. Results:A total of 2,334 DEGs were screened from GSE33294 dataset, including 1,120 up-regulated and 1,214 down-regulated genes. GO, KEGG and GSEA results showed that DEGs are significantly associated with the biological process of cell cycle, cell division and DNA replication. The Kaplan-Meier survival analysis results showed that the key genes from the minichromosome maintenance protein complex (MCM) family including MCM8, MCM10, MCM2, MCM3, MCM4, MCM6 and MCM7 were significantly correlated with the overall survival of the HCC patients. Further validation studies showed that MCM10 was significantly up-regulated in the HCC cell lines, and knockdown of MCM10 significantly suppressed cell proliferation as determined by the cell counting kit-8 and BrdU incorporation assays and increased the caspase-3 activity of HCC cells. Conclusion:The comprehensive bioinformatics analysis identified several key genes that were associated with the prognosis of HCC patients. The validation study results indicated that MCM10 may be an important predictor for poorer prognosis of HCC patients and may act as an oncogene to promote HCC cell progression.

Project description:Objective: To enquire into the clinical significance and potential molecular mechanism of microRNA (miRNA)-196b-5p in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription and polymerase chain reaction (qRT-PCR) were utilized to examine miR-196b-5p expression level in 67 HCC paraffin embedded tissues and corresponding adjacent tissues. Correlations of miR-196b-5p expression level with clinicopathological characteristics were analyzed in our study. The expression level and clinical significance of miR-196b-5p in HCC were also evaluated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We made predictions of the target genes of miR-196b-5p by twelve online software and then selected genes predicted by at least 5 software. Subsequently, in order to obtain the potential target genes of miR-196b-5p, we overlapped the predicted target genes and down-regulated mRNAs in HCC based on TCGA database. Then, we performed the Gene Ontology (GO) and the Disease Ontology (DO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network construction of those miR-196b-5p potential target genes. Results: Higher expression level of miR-196b-5p was seen in HCC tissues than in the corresponding adjacent tissues based on qRT-PCR (P = 0.0007). The expression level of miR-196b-5p was linked with tumor size (P = 0.03), tumor node (P = 0.024), vascular invasion (P = 0.029) and capsular invasion (P = 0.026) in HCC patients. Comprehensive meta-analysis of miR-196b-5p expression based on TCGA, GEO and qRT-PCR verified that higher expression level of miR-196b-5p was observed in HCC tissues than in normal control liver tissues (SMD = 0.56, 95%CI: 0.39-0.72, P heterogeneity = 0.275, I2 = 18.3%). GO annotation revealed that the top terms in biological process, cellular component and molecular function were single-organism catabolic process, neuronal cell body and transmembrane receptor protein kinase activity, respectively. The most relevant disease in DO annotation was arteriosclerosis. The tryptophan metabolism pathway ranked first in KEGG pathway enrichment analysis. The PPI network showed that IGF1, FOXO1, AR and FOS were mostly likely to become the core genes of miR-196b-5p potential target genes, which however required further experiments for validation. Conclusion: The miR-196b-5p was observed to show higher expression in HCC tissues than in normal control liver tissues. Moreover, the miR-196b-5p expression level had correlations with the clinicopathological parameters such as vascular invasion of HCC, but the molecular mechanisms of miR-196b-5p in HCC still need further elucidation and verification.

Project description:ATPase family AAA domain-containing protein 2 (ATAD2), a chromatin regulator and an oncogenic transcription cofactor, is frequently overexpressed in many cancers, particularly in hepatocellular carcinoma (HCC). By integrating open-access online mRNA datasets and our institutional tissue data on HCC, the clinical role and functions of ATAD2 were analyzed by bioinformatic algorithms. We systematically examined ATAD2 expression in HCC based on a large sample population, integrating data from our institution and the GEO, Oncomine, and TCGA datasets. Aberrant ATAD2 expression related to pathways was identified by bioinformatic algorithms. The effects of ATAD2 downregulation on the cycle cell were also determined. A pooled analysis from 28 datasets indicated that ATAD2 overexpression was found in HCC (SMD = 8.88, 95% CI: 5.96-11.81, P < 0.001) and was correlated with poor survival. Subgroup analysis of Asian patients with a serum alpha-fetoprotein (AFP) concentration < 200 ng/ml in stage I + II showed that the ATAD2-high group had a more unfavorable overall survival (OS) rate than the ATAD2-low group. The receiver operating characteristic curve indicated that the efficiency of ATAD2 for HCC diagnosis was considerable (area under the curve = 0.89, 95% CI: 0.86-0.91). Functional analysis based on bioinformatic algorithms demonstrated that ATAD2 participates in cell division, mitotic nuclear division, DNA replication, repair, and cell cycle processes. ATAD2 knockout in HCC cells downregulated cyclin C and cyclin D1 protein levels and resulted in G1/S phase arrest in vitro. The kinesin family member C1 (KIFC1), shugoshin 1 (SGO1), GINS complex subunit 1 (GINS1), and TPX2 microtubule nucleation factor (TPX2) genes were closely related to ATAD2 upregulation. ATAD2 may interact with TTK protein kinase (TTK) to accelerate HCC carcinogenesis. ATAD2 plays a vital role in HCC carcinogenesis by disturbing the interaction between chromatin proteins and DNA. Targeting ATAD2 represents a promising method for the development of therapeutic treatments for cancer.

Dataset Information

Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance.

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Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance.

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