title: Upregulation of MicroRNA-19b predicts good prognosis in patients with hepatocellular carcinoma presenting with vascular invasion or multifocal disease.
abstract: BACKGROUND
  After surgical resection of hepatocellular carcinoma (HCC), recurrence is common, especially in patients presenting with vascular invasion or multifocal disease after curative surgery. Consequently, we examined the expression pattern and prognostic value of miR-19b in samples from these patients.
  
  
  METHODS
  We performed a miRNA microarray to detect differential expression of microRNAs (miRNAs) in 5 paired samples of HCC and non-tumoral adjacent liver tissue and a quantitative real-time polymerase chain reaction (PCR) analysis to validate the results in 81 paired samples of HCC and adjacent non-tumoral liver tissues. We examined the associations of miR-19b expression with clinicopathological parameters and survival. MiR-19b was knocked down in Hep3B and an mRNA microarray was performed to detect the affected genes.
  
  
  RESULTS
  In both the miRNA microarray and real-time PCR, miR-19b was significantly overexpressed in the HCC tumor compared with adjacent non-tumor liver tissues (P < 0.001). The expression of miR-19b was significantly higher in patients who were disease-free 2 years after surgery (P < 0.001). High miR-19b expression levels were associated with higher α-fetoprotein levels (P = 0.017). In the log-rank test, high miR-19b was associated with better disease-free survival (median survival 37.107 vs. 11.357; P = 0.022). In Cox multivariate analysis, high miR-19b predicted better disease-free survival and overall survival (hazards ratio [HR] = 0.453, 95 % confidence interval [CI] = 0.245-0.845, P = 0.013; HR = 0.318, CI = 0.120-0.846, P = 0.022, respectively). N-myc downstream regulated 1 (NDRG1) was downregulated, while epithelial cell adhesion molecule (EPCAM), hypoxia-inducible factor 1-alpha (HIF1A), high-mobility group protein B2 (HMGB2), and mitogen activated protein kinase 14 (MAPK14) were upregulated when miR-19b was knocked down in Hep3B.
  
  
  CONCLUSIONS
  The overexpression of miR-19b was significantly correlated with better disease-free and overall survival in patients with HCC presenting with vascular invasion or multifocal disease after curative surgery. MiR-19b may influence the expression of NDRG1, EPCAM, HMGB2, HIF1A, and MAPK14.
authors.affiliation: Division of Oncology and Hematology, Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, 600, Taiwan. samhong1111@gmail.com.
authors.forename: Chung-Lin
authors.initials: CL
authors.lastname: Hung
authors.affiliation: Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 704, Taiwan. svsycs@gmail.com.
authors.forename: Chia-Shen
authors.initials: CS
authors.lastname: Yen
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan. hungwen@mail.ncku.edu.tw.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: Division of Hematology-Oncology, Buddhist Dalin Tzu Chi Hospital, Taiwan, ROC. hepatoma@gmail.com.|School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC. hepatoma@gmail.com.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Su
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 704, Taiwan. yencj@mail.ncku.edu.tw.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000150:complications / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000401:mortality* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D047368:Tumor Burden
chemical_list: C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger