Expression And Clinical Significance Of Ras,Raf-1,pMEK1 And PERK 1/2 In Hepatocellular Carcinoma

【Objective】Hepatocellular carcinoma(HCC) is the fifth most common cancer worldwide and the most common malignant primary tumour in the liver.The Ras/Raf/MEK/ERK pathway is a component of the mitogen activated protein kinase (MAPK) cascade and is activated by extracellular and intracellular.It played an important regulatory role in cell cycle regulation,cell proliferation,cell apoptosis, cellular growth inhibiting and differentiation.This cascade was an essential oncogenic progression.Our research is to study the expression of Ras,Raf-1,pMEK1 and pERK1/2 in HCC and non-cancerous adjacent liver,and evaluate the relationship of Ras,Raf-1,pMEK1 and pERK1/2 in the tumorigenesis and development of HCC. Meanwhile,our study is to discuss the clinicopathologic factors and to analyze the survival time of patients so as to provide theoretical basis for prevention,treatment and prognosis of HCC.【Methods】The cases who received surgery therapy in our hospital from 2000.1 to 2006.12 and were diagnosed with HCC.We detected the expression of Ras,Raf-1,pMEK1 and pERK1/2 in liver cancer tissue and non-cancerous adjacent liver tissue by immunohistochemistry method(PV6000).To analyze the relationship between Ras,Raf-1,pMEK1 and pERK1/2 and the clinicopathologic index of HCC byχ~2 test,and analyze the relationship of Ras,Raf-1,pMEK1 and pERK1/2 by Spearman interclass correlation.Single factor survival analysis by Kaplan-Meier,survival curve by Log-Rank test.To analyze the factors correlating with the prognosis by Cox proportional hazard regression model.These results were analyzed by SPSS17.0 statistical software package,a P-value less than 0.05 were considered significant. 【Results】1.79 cases were employed.Untill the destinaion of study,There were 45 cases dead.The median overall survival(OS) was 37.4months.The median progression survival(PFS) was 29.2months.The early clinical stage,the well-differentiated of histological grade,the solitary tumor and without portal thrombi were better.There were no correlation between the prognosis of patients and gender,age of patients,the value of AFP,HBsAg,size of tumour and hepatocirrhosis.Cox proportional hazard regression model showed that the number of tumor(P=0.004),the clinical stage (P=0.002) and the histological classification(P=0.001) were the significant prognostic factors of PFS in postoperative HCC patients.The recurrence and metastasis within 2 years(P=0.002),the histological classification(P=0.000),the clinical stage(P=0.001) were the significant prognostic factors of OS(P＜0.05).2.The positive expression rate of Ras was 27.8%in HCC.There was no significant difference between liver tissue and non-cancerous tissue in which the positive expression rate of Ras was 19.0%.The MST with over-pression of Ras was 24.6 months and the PFS was 20.5 months.The MST with weak-expression of Ras was 48.8 months and the PFS was 37.4 months.There was significant difference of the survival time between two groups(P＜0.05),however,there was no significant difference of PFS between them(P＞0.05).3.The positive expression rate of Raf-1 was 46.8%and non-cancerous adjacent liver tissue was 11.4%,there was significant difference.The expression of Raf-1 was significant correlation with the histological classification(P＜0.05).The MST in weak-expression of Raf-1 was significant longer than over-expression group(not available vs 25.2months,p=0.010).The PFS in weak-expression of Raf-1 was significantly longer than over-expression group also(44.8 months VS 21.9 months, P=0.009).4.The positive expression rate of pMEK1 in HCC was 63.3%and non-adjacent liver tissue was 70.9%.The test showed that it was no significant difference between them.The age and histological classification were correction with the overpression of pMEKI(P＜0.05).The median survival time and the progression free time of weak-expression group were significantly longer than the over-expression group(not available vs 24.9months;51.6 months vs 22.3 months).5.The positive expression rate of pERK1/2 in HCC was 27.8%and non-adjacent liver tissue was 11.1%.There was significantly difference between them.There maybe have some correction between the positive expression of pERK1/2 and OS(P=0.051). However,there was no significant correction between the positive expression of pERK1/2 andPFS(P=0.309).6.Our study showed that there were no significant positive correlation between the expression of Ras,Raf-1,pMEK1 and pERK1/2 in HCC(P＞0.05 ).The collective expression of Ras,Raf-1,pMEK1 and pERK1/2 would show more obvious significance than single expression of them.Cox proportional hazard regression model showed that:the positive expression of Ras,Raf-1 and pMEK1 in HCC were independent risk factors affecting the prognosis of HCC(P＜0.05).【Conclusions】The early clinical stage,the well-differentiated of histological classification,the solitary tumor and without portal thrombi were better.Cox proportional hazard regression model showed that the number of tumor,the clinical stage,the histological classification and the recurrence and metastasis within 2 years were independent risk factors affecting the prognosis of HCC.The expression of Ras and pMEK1 was no significantly difference between the live tissue and non-adjacent liver tissue.The expression of Raf-1 and pERK1/2 was significantly difference between the live tissue and non-adjacent liver tissue.The median survival time and the progression free time of patients with over-expression of Ras,Raf-1 and pMEK1 in HCC was shorter than the weak-expression groups.The prognostic of them was poor. There was no significant positive correlation between the expression of Ras,Raf-1,pMEK1 and pERK1/2 in HCC.Cox proportional hazard regression model showed that the positive expression of Ras,Raf-land pMEK1 in HCC were independent risk factors affecting the prognosis of patients with HCC.