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

J Hepatol. 2008 Jan;48(1):83-90. doi: 10.1016/j.jhep.2007.08.018. Epub 2007 Oct 29.


Background/aims: 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.

MeSH terms

  • Adult
  • Alcoholism / complications
  • Alcoholism / pathology
  • Carcinoma, Hepatocellular / pathology*
  • Cohort Studies
  • Enzyme Activation / physiology
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Hepatectomy
  • Hepatitis B / complications
  • Hepatitis B / pathology
  • Hepatitis C / enzymology*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Liver Diseases, Alcoholic / complications
  • Liver Diseases, Alcoholic / pathology
  • Liver Neoplasms / pathology*
  • Liver Transplantation
  • Male
  • Microarray Analysis
  • Oncogene Protein v-akt / physiology*
  • Prognosis
  • Signal Transduction / physiology*
  • Survival Analysis


  • ErbB Receptors
  • Oncogene Protein v-akt
  • Extracellular Signal-Regulated MAP Kinases