title: Clinical significance of the ubiquitin ligase UBE3C in hepatocellular carcinoma revealed by exome sequencing.
abstract: Virus-induced hepatocarcinogenesis involves a series of histological developmental processes with the stepwise acquisition of several genetic changes that are necessary for the malignant transformation of hepatocytes. Although genetic alterations are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC), little is known about the contributions of specific genes to this process. To gain insight into the genetic alterations involved in the neoplastic evolution from chronic hepatitis B virus infection to dysplastic nodules (DN) to HCC, we captured and sequenced the exomes of four DNA samples: one DN sample, two HCC samples, and one control peripheral blood sample from a single HCC patient. Mutations in the UBE3C gene (encoding ubiquitin ligase E3C) were observed in both tumor tissues. Then we resequenced the UBE3C gene in a cohort of 105 HCC patients and identified mutations in 17 out of a total of 106 (16.0%) HCC patients. The subsequent experiments showed that UBE3C promoted HCC progression by regulating HCC cells epithelial-mesenchymal transition. Clinically, a tissue microarray study of a cohort containing 323 HCC patients revealed that the overexpression of UBE3C in primary HCC tissues correlated with decreased survival (hazard ratio [HR] =1.657, 95% confidence interval [CI] =1.220-2.251, P=0.001) and early tumor recurrence (HR=1.653, 95% CI=1.227-2.228, P=0.001) in postoperative HCC patients.
  
  
  CONCLUSIONS
  Our findings indicate that UBE3C is a candidate oncogene involved in tumor development and progression and therefore a potential therapeutic target in applicable HCC patients.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Jiang
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Liu
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Gu
authors.forename: Yao
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Guo-Ming
authors.initials: GM
authors.lastname: Shi
authors.forename: Bo-Yi
authors.initials: BY
authors.lastname: Liao
authors.forename: You-Hua
authors.initials: YH
authors.lastname: Xie
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D059472:Exome / Q000235:genetics*; D005260:Female; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D011379:Prognosis; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C555759:UBE3C protein, human; D044767:Ubiquitin-Protein Ligases