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☆
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the most common malignant primary tumour in the liver [1]. The major clinical HCC risk factor is liver cirrhosis with about 70–90% of HCCs developing in cirrhosis [2]. The prognosis of HCC is generally poor but longer survival can be achieved in patients with localized HCC which can be treated by liver resection or liver transplantation. However, the majority of patients already show at the time of diagnosis advanced stage disease with markedly reduced 5-year survival. Thus, besides the potentially curative surgical therapies, there is an urgent need for novel therapeutic approaches for this highly aggressive liver tumour.
Recently protein kinases have emerged as a group of molecular targets allowing the development of a new generation of chemotherapy agents which inhibit these kinases. Promising targets in this context are kinases involved in the MAPK and AKT/PI3K pathway [3], [4]. The ERK pathway is a component of the mitogen activated protein kinase (MAPK) cascade and is activated by extracellular and intracellular, frequently mitogenic, ligands including PDGF, VEGF and EGF [5], [6], [7]. The ERK signalling module consists of two isoenzymes, namely ERK1/2, also called p44ERK1 and p42ERK2. Activated ERK1/2 translocate into nuclei [8] and induce/activate transcription factors such as c-Fos and c-Jun [9] which in turn increase transcriptional activity of genes relevant for cell cycle progression such as Cyclin D1 [10].
Human HCC was shown to exhibit high expression and enhanced activity of MAP kinase compared to non-neoplastic liver [11], [12]. In vitro studies demonstrated that treatment with a MAP kinase inhibitor reduced cell proliferation and induced apoptosis [13]. Moreover overexpression of MAP kinase (MEK1) in HepG2 carcinoma cells enhanced tumour growth in vivo[14]. Factors activating the ERK1/2 pathway such as EGFR frequently induce another central signalling pathway, namely the AKT pathway. AKT/protein kinase B (PKB) plays a critical role in controlling the balance between cell survival and apoptosis [15], [16]. AKT phosphorylation is mediated by phosphatidylinositol-3-OH-kinase (PI3K) in response to various growth/survival factors and activation of the pathway is crucial for tumour cell survival.
The present study elucidates the prognostic relevance of the ERK and AKT pathway in HCC. Additionally we investigated EGFR expression and monitored functional effects of ERK and AKT such as tumour cell proliferation and apoptosis. Finally we analysed pAKT and pERK expression in HCC in relation to the presence of HBV, HCV infection or chronic alcohol abuse.
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Material and methods
The complete cohort consisted of 208 patients with histologically proven HCC. The tumours were classified according to the WHO classification and staged by means of the pTNM system [17]. Detailed clinical data were available for both the transplantation group (99 patients) and the resection group (109 patients); data were completed by December 2006. Data about the underlying viral infection (Hepatitis B or C) or etiologic factors of non-viral induced cirrhosis (e.g. ethanol abuse and other
Immunohistochemical analysis of phospho-ERK1/2, phospho-AKT and EGFR (resection group)
pERK1/2 immunohistochemistry of HCC revealed a specific cytoplasmic immunostaining with few scattered positive nuclei. Non-neoplastic tissue (n = 4), obtained from patients with resected liver metastasis due to colorectal cancer, revealed no immunostaining. Non-cancerous liver tissue surrounding the HCCs partly revealed a positive pERK immunostaining of the cytoplasm, which became more faint with increasing distance to the tumour. Tumours lacking pERK1/2 staining were classified as negative. 84
Discussion
HCC represents an aggressive cancer with a generally poor prognosis. Although curative treatment options are available, recurrence after curative resection is still high. Thus there is a need for novel therapeutic strategies such as “targeted therapies” inhibiting signalling pathways. Promising candidates are multikinase inhibitors for instance sorafenib, which inhibits several kinases including the raf kinase, an upstream activator of the ERK pathway [19], [20], [21]. A recent study published
Acknowledgement
The technical assistance of Dorothe Möllmann is gratefully acknowledged.
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The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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These authors contributed equally to the study.
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Member of the West German Cancer Centre Essen (WTZE).