Expression And Clinical Significance Of PTPRO In Patients With Hepatocellular Carcinoma

[Objective] Hepatocellular carcinoma(HCC) is one of the most common malignant tumors with limited treatment options. The hepatocarcinogenesis involves a series of mechanisms, such as gene mutation, cellular signal transduction, tumor neovascularization and so on. In the last decades, in addition to genetic alterations, epigenetic inactivation of tumor suppressor genes by promoter hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. We performed the study to detect the protein expression of PTPRO which is considered as a novel candidate tumor suppressor and the methylation conditions of hMLH1 (?) DAPK and GSTP1 in HCC tissues and to determine their clinical significance.[Methods] The study was consisted of 72 patients who had undergone the liver resection for HCC at the Department of Hepticbile Surgery, General Hospital of PLA between January 2000 and December 2005. The expression and distribution of PTPRO protein were examined by immunohistochemistry in HCC and its pericarcinomatous tissues. Nest specific methylation PCR was used for detecting the methylation conditions of hMLH1 (?) DAPK and GSTP1.[Results]1.72 cases were enrolled for the research. Unti1 the destination of study, there were 37 cases dead. The median progress free survival(PFS) and overall survival(OS) time for total patients was 26.3 months and 48.3 months respectively. The results of univariate analysis showed that the patients with well differentiation,early clinical stage,tumor capsule and without portal embolis or progress in the early two years after the operations had the longer median OS time(P<0.05). Patients with solitary tumor,early clinical stage, tumor capsule and without portal embolis had the longer median PFS time(P<0.05). No correlations were found between the prognosis and age, gender, HBsAg, serum AFP level, size of tumor and hepatic cirrhosis. Cox regression model showed that the tumor differentiation (P=0.000), tumor capsule (P=0.003) and the time of recurrence and metastasis (P=0.000) were the significant prognostic factors of OS in postoperative HCC patients. The number of tumor (P=0.045) and the clinical stage (P=0.021) were the significant prognostic factors of PFS.2. Until the destination of study, there were 47 cases of metastasis and recurrence (65.3%),of which the cases within and exceed the early two years after operation were 33(70.2%) and 14(19.4%) respectively. The patients with low differentiation, high AFP level (>400ug/L), portal embolis or progress in the early two years after the operations had the shorter median OS time (P<0.05) Cox regression model showed that the tumor differentiation (P=0.002) and the time of recurrence and metastasis (P=0.001) were the significant prognostic factors of OS in patients with relapse or metastasis after operations. High AFP level (>200ug/L) was the high risk factor of recurrence and metastasis within two years after operations (P=O.O33) Patients with primary symptoms were inclined to a after-two-years'relapse(P=0.033).3. With only one HCC tissue negative, the expression of PTPRO protein was 98.6% in HCC tissues and 100% in pericarcinomatous tissues, both of which were located in the cytoplasm. 18 of 72 HCC tissues(25.0%) and 32 of 72 pericarcinomatous tissues(44.4%) were overexpressed. A significant difference was found between these two groups(P<0.05). The expression of PTPRO is reduced in HCC relative to its pericarcinomatous tissues. The level of the expression of PTPRO was negatively related to hepatic cirrhosis. The overexpression rates of PTPRO in patients with and without hepatic cirrhosis are 15.6% and 40.7%. The difference was considered statistically significant (P=0.017).The expression of PTPRO in patients with hepatic cirrhosis obviously decreased. Univariate and multivariate analyses did not show the correlations between PTPRO expression and prognosis(P>0.05).4. The methylation rates of hMLH1 o DAPK and GSTP1 were 75.4% (?) 98.5% and 71.4% in 65 HCC tissues. All cases existed at least one kind of methylation.34 of 65 HCC cases showed the collective methylation of these three targets. Patients with early clinical stage (P=0.022) and low AFP level(≤400ug/L, P=0.044) had the higher hMLH1 methylation rate. Patients without the clinical symptoms had the higher GSTP1 methylation rate. Patients with methylation of hMLHl and GSTP1 had the longer median PFS (P=0.034) than the both negative ones. The collective methylation of all these three targets was inclined to a less invasion rate of portal embolis.[Conclusions] Patients with well differentiation,early clinical stage,tumor capsule and without portal embolis or progress in the early two years after the operations had the better prognosis. The tumor differentiation, tumor capsule and the time of recurrence and metastasis were the significant prognostic factors of OS in postoperative HCC patients. The number of tumor and the clinical stage were the significant prognostic factors of PFS. The patients with low differentiation, high AFP level (>400ug/L) portal embolis or progress in the early two years after the operations had the worse prognosis。Tumor differentiation and the time of recurrence and metastasis were the significant prognostic factors of OS in patients of the relapse with metastasis following operations. High AFP level (>200ug/L) was the high risk factor of recurrence and metastasis within two years after operations. Patients with primary symptoms were inclined to a after-two-years'relapse. The expression of PTPRO is reduced in HCC relative to its pericarcinomatous tissues. The level of the expression of PTPRO was negatively related to hepatic cirrhosis. The expression of PTPRO in patients with hepatic cirrhosis obviously decreased. Patients with early clinical stage and low AFP level(≤400ug/L) had the higher hMLHl methylation rate; Patients without the clinical symptoms had the higher GSTP1 methylation rate; Patients with collective methylation of hMLHl and GSTP1 had the longer median PFS than the both negative ones. The collective methylation of all these three targets was inclined to a less invasion rate of portal embolis.