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.
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.
Schmitz
Klaus Juergen
KJ
Institute of Pathology and Neuropathology, University Hospital of Essen, Germany.
Wohlschlaeger
Jeremias
J
Lang
Hauke
H
Sotiropoulos
Georgios Charalambos
GC
Malago
Massimo
M
Steveling
Karen
K
Reis
Henning
H
Cicinnati
Vito Rosario
VR
Schmid
Kurt Werner
KW
Baba
Hideo Andreas
HA
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
D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases