Expression and Prognostic Role of Pan-Ras, Raf-1, PMEK1 and PERK1/2 in Patients with Hepatocellular Carcinoma

Aims: Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascades play important roles in the transmission of signals involved in apoptosis. Importantly, components of these pathways are aberrantly expressed in human cancer. However, there is limited data linking clinical outcomes with the aberrant expression of this pathway. The present study analyzed the prognostic values of pan-Ras, Raf-1, phosphorylated MEK1 (pMEK1) and phosphorylated ERK1/2 (pERK1/2) in hepatocellular carcinoma (HCC).

Methods: Expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 in 81 HCC patients who underwent curative resection was examined by immunohistochemical staining. Long-term survival after resection of patients according to the expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 was assessed using univariate analysis and multiple Cox proportional hazards model.

Results: In univariate analysis, patients with Raf-1 or pMEK1 overexpression had shorter disease-free survival (DFS) (P<0.05) and poorer overall survival (OS) (P<0.05) than groups with weak-expression of Raf-1 or pMEK1, respectively. Patients with pan-Ras overexpression had poorer overall survival (OS) (P<0.05) than the group with weak-expression of pan-Ras. Importantly, Raf-1 overexpression was a promising prognostic marker for poor survival according to multivariate Cox regression analysis (DFS, Hazard Ratio 1.807, P = 0.035; OS, Hazard Ratio 1.959, P = 0.044).

Conclusions: Raf-1 overexpression could be considered as an independent prognostic biomarker in HCC and may predict early tumor recurrence and death for HCC patients. It can be used to stratify patients at higher risk for poor prognosis and help to select the appropriate therapeutic regime of HCC.