title: Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection.
abstract: OBJECTIVE
  The aim of the study was to determine the prognostic relevance of AKT and extracellular regulated kinases (ERK1/2), which are implied in the regulation of cell proliferation and apoptosis, in hepatocellular carcinoma (HCC).
  
  
  METHODS
  This study comprised a series of 208 patients incorporating HCCs treated either by surgical resection (n = 109) or liver transplantation (n = 99). Immunohistochemically demonstrated phospho-ERK1/2 (pERK1/2) and phospho-AKT (pAKT) was correlated with a series of clinico-pathologically relevant parameters (EGFR, Cyclin-D1, HCV/HBV infection, liver cirrhosis, chronic alcohol abuse), proliferative activity, and apoptosis.
  
  
  RESULTS
  Activation of ERK1/2 correlated statistically with the presence of HCV infection. pERK1/2 (P < 0.001) and pAKT (P = 0.052) expression showed a significant correlation with a decreased overall survival (OS). In multivariate Cox regression analysis pERK1/2 was identified as an independent prognostic parameter in HCC (P = 0.026).
  
  
  CONCLUSIONS
  Activation of ERK1/2 in HCC cancer indicates aggressive tumour behaviour and constitutes an independent prognostic factor. Furthermore our data confirm that HCV infection activates the ERK pathway and thereby might contribute to HCC carcinogenesis. Immunohistochemical determination of pERK1/2 status can thus be proposed as a promising candidate for the identification of high risk patients who may benefit from new anticancer drugs targeting the ERK-pathway.
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Essen, Germany.
authors.forename: Klaus Juergen
authors.initials: KJ
authors.lastname: Schmitz
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Hauke
authors.initials: H
authors.lastname: Lang
authors.forename: Georgios Charalambos
authors.initials: GC
authors.lastname: Sotiropoulos
authors.forename: Massimo
authors.initials: M
authors.lastname: Malago
authors.forename: Karen
authors.initials: K
authors.lastname: Steveling
authors.forename: Henning
authors.initials: H
authors.lastname: Reis
authors.forename: Vito Rosario
authors.initials: VR
authors.lastname: Cicinnati
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Hideo Andreas
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000150:complications / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D015331:Cohort Studies; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006498:Hepatectomy; D006509:Hepatitis B / Q000150:complications / Q000473:pathology; D006526:Hepatitis C / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology*; D016031:Liver Transplantation; D008297:Male; D046228:Microarray Analysis; D051058:Oncogene Protein v-akt / Q000502:physiology*; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis
chemical_list: D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases