Expression And Significance Of Eukaryotic Initiation Factor 4E, HPA And MMP9 In Human Astrocytoma

Objective: Astrocytoma is the most common human brain tumor, accounting for about 35.26%~60.96% of all brain tumors in our country. The biological behavior of astrocytoma is quite special. All the astrocytomas, whether well differentiated or poor differentiated, show invasive growth pattern. The therapeutic effects of surgical, chemotherapeutical, and radiotherapeutical treatment are not good enough usually because of local recurrence and invasive growth.Eukaryotic initiation factor 4E (eIF4E) is a polypeptide of 25×103, and it plays an important regulative role in the initiation of protein synthesis. eIF4E is expressed relatively low in the normal tissues. eIF4E was involved in the competition between strong and weak RNAs. The"strong mRNA", mostly with the short 5'-UTR (untranslated region) and"house-guard"function, competes with the"weak mRNA"(tumor related RNA), usually with the long 5'-UTR. When the eIF4E is in the normal level, the former gains the advantage, resulting in the inhibition of the translation of"weak mRNA". The inhibition stops only when the eIF4E is overexpressed. The overexpression of eIF4E leads to the up-regulation of the several gene products of the"weak mRNA"with the long 5'-UTR, which were not translated in normal condition. The gene products include heparanase (HPA), matrix metalloproteinases 9 (MMP9), Cyclin D1, C-myc as well as TNF–α, etc. Both HPA and MMP 9 are matrix catabolic enzymes and may play a very important role in the invasion and metastasis of malignant tumors through degradation of extracelluler matrices (ECM) and basement membrance (BM) of cancer cells.The overexpression of eIF4E has been identified in many human tumours, such as breast cancer, squamous cell carcinoma in head and neck, colon carcinoma, prostate carcinoma, bladder carcinoma, cervicis cancer, lung cancer, leukemia etc. The overexpression of eIF4E is closely related with the progression of the malignancies. Up to now, few works have been seen on the expression and the putative role of eIF4E in brain astrocytoma. Thus, it is of important value to explore the possible relationship between eIF4E expression and tumorigenesis and the unique biological behavior in astrocytoma.Method: Archival paraffin embedded tissue blocks of astrocytoma with original clinical and pathological records and normal brain tissue from the Department of Pathology of the Second Hospital, Hebei Medical University in the period of Dec, 2004 to Jan, 2006 were included in this study. All the slides of the cases were reviewed by two experienced pathologists according to 2000 WHO criterion and the diagnosis confirmed. Among the 63 cases of astrocytomas, 21 cases were gradeⅡ, 24 cases were gradeⅢ, and the other 18 cases were gradeⅣ. The 20 cases of normal brain tissue were from the patients with brain accidents.The expression of eIF4E, HPA and MMP9 was immunohistochemically studied in 63 cases of astrocytoma of different grade and 20 cases of normal brain tissue with ElivisionTM plus two-step method. The relationship and significance of eIF4E, HPA and MMP9 on the tumorigenesis and invasive growth of astrocytoma was analyzed.The experimental data were statistically analyzed with SPSS 11.0 edition.Results:1 The expression of eIF4E in brain astrocytoma and normal brain tissueThe positive expression of eIF4E could be seen in all the neurons of brain tissue. Of the 20 brain tissue, showed no positive eIF4E expression in neuroglial cells. Among the 63 cases of astrocytoma, 43 cases showed positive expression of eIF4E. The positive expression rate of eIF4E in astrocytoma was 68.25% (43/63), which was significantly higher than that in normal brain tissue (χ2=28.325, P<0.05). The positive expression rate of eIF4E in grade II, III and IV astrocytoma was 38.10%, 75.00% and 94.44% repectively. Significant differences in the expression of eIF4E were found among astrocytoma of different grades (χ2=15.017, P<0.05). The expression of eIF4E in gradeⅢand IV cases was significantly higher than that in gradeⅡ(χ2=6.253, P<0.05 andχ2=13.375, P<0.05). No statistical difference was found between gradeⅢand gradeⅣ(χ2=1.575, P>0.05).2 The expression of HPA in brain astrocytoma and normal brain tissueNo positive expression of HPA was found in normal brain tissues (0%,0/20). The positive expression rate of HPA in 63 astrocytoma was 80.95% (51/63), which was significantly higher than that in normal brain tissues (χ2=41.994, P<0.05). The positive expression rate of HPA was 61.90%, 87.50% and 94.44% for gradeⅡ,ⅢandⅣcases respectively. The positive expression rate of HPA in gradeⅢand gradeⅣastrocytoma cases was significant higher than that in gradeⅡ(χ2=3.973, P<0.05 andχ2=5.781, P<0.05). While no significant difference in the HPA expression was seen between gradeⅢand gradeⅣ(χ2=0.576, P>0.05).3 The expression of MMP9 in brain astrocytoma and normal brain tissueMMP9 was negatively expressed in all of the 20 normal brain tissues (0%,0/20). The positive expression rate of MMP9 in astrocytoma was 65.08% (41/63), which was significantly higher than that in normal brain tissues (χ2=25.722, P<0.05). The positive expression rate of MMP9 increased as the grade of astrocytoma increased. The positive expression rate was 33.33% (gradeⅡ), 70.83% (gradeⅢ) and 94.44% (gradeⅣ) respectively. Statistical analysis results showed that significant differences were found between gradeⅡand gradeⅢ/Ⅳastrocytomas (χ2=6.328, P<0.05 andχ2=15.293, P<0.05), while no statistical difference was seen between gradeⅢand gradeⅣcases (χ2=0.000, P>0.05).4 Relationship among eIF4E, HPA and MMP9 expressions in astrocytomaAmong 43 eIF4E positive expression astrocytoma cases, 39 cases showed HPA positive expression (90.70%), while HPA positive expression could be found in 12 of the 20 eIF4E negative expression cases (60.00%). Statistical analysis showed that there was positive correlation between eIF4E and HPA expression in astrocytoma (χ2=8.210, P<0.05).The MMP9 positive expression rate among the eIF4E positive and negative expression cases were 76.74% (33/43) and 40.00% (8/20) respectively. The MMP9 expression was positively correlated with that of eIF4E in astrocytoma (χ2=7.981, P<0.05).The positive expression of MMP9 and HPA was also positive related in astrocytoma. MMP9 positive expression could be seen in 37 cases among the 51 HPA positive expression cases and only 4 cases were positive for MMP9 in the 12 HPA negative expression cases (χ2=6.469, P<0.05).Conclusions:1 The immunohistochemical results in this study showed that the positive expression rate of eIF4E in astrocytoma was significantly higher than that in normal brain tissue. And the eIF4E positive expression was significantly increased as the pathological grade of the astrocytoma increased, suggesting that eIF4E be related to the tumorigenesis and progression of astrocytoma in brain.2 No positive expression of HPA and MMP9 could be seen in normal brain tissue. The positive expression rate of HPA and MMP9 were increased significantly in astrocytoma, which may be related with the invasive growth pattern of astrocytoma.3 The expression of eIF4E was positively related with that of HPA and MMP9 in astrocytoma. Thus, it seem that eIF4E, HPA and MMP9 were all take part in the invasive growth of astrocytoma.