title: 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.
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Ke-Qing
authors.initials: KQ
authors.lastname: Shi
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Xiang-Jian
authors.initials: XJ
authors.lastname: Chen
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Yu-Qun
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Yi-Jing
authors.initials: YJ
authors.lastname: Cai
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Nai-Bing
authors.initials: NB
authors.lastname: Yang
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Zheng
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Jin-Zhong
authors.initials: JZ
authors.lastname: Dong
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D019295:Computational Biology; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012307:Risk Factors; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: biomarker; hepatocellular carcinoma; microRNA; robust rank aggregation; signature