title: Prognostic significance of synergistic hexokinase-2 and beta2-adrenergic receptor expression in human hepatocelluar carcinoma after curative resection.
abstract: BACKGROUND
  Hexokinase-2 (HK2) and Beta2-adrenergic receptor (Beta2AR) are overexpressed in hepatocellular carcinoma (HCC) tissues and associated with poor prognosis. However, the synergistic effect of HK2 and Beta2AR in HCC prognosis is not elucidated. The present study aims to investigate the association between HK2 and Beta2AR expressions in HCC tissues, and to evaluate the synergistic effect of HK2 and Beta2AR in HCC prognosis.
  
  
  METHODS
  Immunohistochemistry of HK2 and Beta2AR was performed on 155 paraffin embedded HCC samples retrieved from the archives of pathology department. Corresponding clinical data and prognostic data were collected through searching medical record systems, death registration systems and interviews with patient families. Spearman correlation test was performed to evaluate the association between HK2 and Beta2AR expression. Kaplan-Meier survival curves and Cox regressions were employed to evaluate HK2 and Beta2AR expression in HCC prognosis, respectively and synergistically.
  
  
  RESULTS
  109 of 155 HCC patients reached the death point, the survival time of HCC patients was 46.23 ± 31.01 months after curative surgical resections of HCC. Kaplan-Meier survival analysis showed that large tumor size (more than 5 cm) (hazard ratio (HR) = 8.42, 95 % confidence interval (CI) = 3.81-18.59, P < 0.0001), advanced TNM stage (III and IV stages) (HR = 2.09, 95%CI = 1.21-3.62, P < 0.001) and AFP more than 20 μg/L (HR = 1.49, 95%CI = 1.02-2.18, P = 0.0302) were predictors for poor prognosis. HK2 and Beta2AR positive expression was detected in 66 (42.58) and 122 (78.71 %) HCC samples respectively. In univariate analysis, HK2(+) (HR = 2.70, 95%CI = 1.76-4.15, P < 0.0001) and Beta2AR(+) (HR = 4.61, 96%CI = 3.14-6.76, P < 0.0001) were associated with poor prognosis. In multivariate analysis, HK2(+) (P < 0.0001) and Beta2AR(+) (P < 0.0001) were also associated with poor prognosis. HK2(+)/Beta2AR(+) in HCC samples had poorer prognosis compared with HK2(-)/Beta2AR(-) in both univariate analysis (HR = 4.69, 95%CI = 2.91-7.57, P < 0.0001) and multivariate analysis (P < 0.0001). HK2(+)/Beta2AR(+) in HCC samples had poorer prognosis compared with HK2(-)/Beta2AR(+) in both univariate analysis (HR = 1.76, 95%CI = 1.17-2.64, P = 0.003) and multivariate analysis (P = 0.004).
  
  
  CONCLUSIONS
  HK2 and Beta2AR play important roles in HCC progression. HK2 and Beta2AR expression in HCC is correlated positively. Beta2AR may increase HCC invasion and metastasis in collaboration with HK2. HK2 and Beta2AR can predict HCC prognosis both independently and synergistically.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Xiao-Sha
authors.initials: XS
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: He
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China. cathydoctor@sina.com.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Duan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Pi-Xu
authors.initials: PX
authors.lastname: Liu
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Qiu-Ping
authors.initials: QP
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Jin
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Sun
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, 116000, Dalian, Liaoning Province, China.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000601:surgery*; D004357:Drug Synergism; D005260:Female; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D018343:Receptors, Adrenergic, beta-2; D006593:Hexokinase
keywords: Beta2-adrenergic receptor; Hepatocellular carcinoma; Hexokinase-2; Immunohistochemistry; Prognosis