title: Integrated analysis of miRNA, gene, and pathway regulatory networks in hepatic cancer stem cells.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. HCC has a poor prognosis associated with tumor recurrence and drug resistance, which has been attributed to the existence of hepatic cancer stem cells (HCSCs). However, the characteristics and regulatory mechanisms of HCSCs remain unclear. We therefore established a novel system to enrich HCSCs and we demonstrate that these HCSCs exhibit cancer stem cell properties.
  
  
  METHODS
  We used miRNA and mRNA high-throughput sequencing data sets to determine molecular signatures and regulatory mechanisms in HCSCs. Paired miRNA and gene deep sequencing data in HCSCs versus HCC cells were used to identify candidate biomarkers of HCSCs. Using network analysis, we studied the relationship between miRNA and gene biomarkers, and KEGG pathway enrichment analysis was performed to study the function of candidate biomarkers.
  
  
  RESULTS
  We identified 9 up- and 9 down-regulated miRNAs and 115 up- and 402 down-regulated genes in HCSCs compared with HCC cells. A miRNA-gene network was constructed using 651 miRNA-gene interactions (between 7 up-regulated miRNAs and 274 down-regulated genes), and 103 miRNA-gene interactions (between 9 down-regulated miRNAs and 62 up-regulated genes). Pathway enrichment analysis identified five tumor invasion- and metastasis-related pathways and MAPK signaling associated with HCSCs. We further discovered two novel pathways that likely play a role in the regulation of HCSCs.
  
  
  CONCLUSIONS
  We identified a molecular expression signature and pathway regulatory mechanisms in HCSCs with potential diagnostic and therapeutic value.
authors.affiliation: Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. dingmin0326@hotmail.com.
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. iamlijiang@hotmail.com.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. yluobosi@126.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. liuhui110120@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. yanzi0580@gmail.com.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yan
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. wangjh201011@hotmail.com.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, People's Republic of China. qianqj@sino-gene.com.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs