Expression Of EZH2, P130 And P16 In Endometrial Carcinogenesis

Objective: Endometrial carcinoma is the common malignant neoplasm in female reproductive system. The carcinogenesis and progression of endometrial carcinoma is a very complicated process, involving the activation of oncogenes, the inactivation and mutation of tumor suppressor gene, antiapoptosis mechanisms, etc. Endometrial hyperplasia-atypical hyperplasia-adenocarcinoma is usually considered as the typical carcinogenic sequence of endometrial carcinoma. Endometrial hyperplasia, especially, atypical hyperplasia, is the precancerous lesion of endometrial carcinoma. Thus, study of the carcinogenesis would be very important for the effective prevention and treatment of endometrial carcinoma.The human homolog of the Drosophila Enhancer of zeste gene (EZH2), as a novel gene, was discovered in 1996, mapping on human chromosome 7q35. The EZH2 gene is associated with regulation of cell growth. EZH2 could promote the cell proliferation by inhibiting the target genes in eukaryotic chromatin. The pRb-E2F pathway is best known for its role in the regulation of cell proliferation and tumorgenesis. The EZH2 is located in the downstream of the pRb-E2F pathway. The dephosphorylated pRb binds with E2F and the pRb-E2F could inhibit the transcription of the promoter of EZH2. The down-regulated expression of EZH2 inhibits cell growth via G2/M arrest.Amplification of EZH2 has been confirmed by fluorescence in situ hybridization (FISH) in several cancers. Thus, EZH2 is considered as a strong candidate oncogene. At genetic level, EZH2 as a transcription inhibitor can suppress lots of the genes, especially the metastasis-suppressing genes, promoting invasion and metastases of tumor cells. p130 is a typical tumor suppressor gene belonging to Rb gene family, and p16, also called mutiple tumor suppressor (MTS), is also a tumor-suppressor gene. Under physical condition, p130 and p16 affected the transcription of EZH2 via regulation of the activity of E2Fs. The expression of p130 and p16 results in inhibition of E2F activity and subquent cell cycle arrest.Studies showed that abnormal expression of EZH2 was closely related with the development of leukemia and metastasis of prostate carcinoma. Up to now, few works have been found on the significance of the EZH2 protein in the carcinogenesis of endometrial carcinoma. This study was aim to explore the putative role of EZH2, p130 and p16 in the carcinogenesis of endometrial carcinoma by studying their expressions in normal proliferative endometrium, simple endometrial hyperplasia, complex endometrial hyperplasia, atypical endometrial hyperplasia and endometrial carcinoma. Methods: The expression of EZH2, p130 and p16 in 20 cases of proliferative endometrium, 20 cases of simple endometrial hyperplasia, 20 cases of complex endometrial hyperplasia, 20 cases of atypical endometrial hyperplasia and 43 cases of endometrial adenocarcinoma were examined by immunohistochemistry and the correlation between their expression and the clinicipathological factors were analyzed.Results:1 The expression of EZH2 protein in different groupsEZH2 positive immunoreaction was located in the nucleus of cells as granular brown staining. The positive expression rate of EZH2 in proliferative endometrium, simple endometrial hyperplasia, complex endometrial hyperplasia, atypical endometrial hyperplasia and endometrial adenocarcinoma was 15.0%, 30.0%, 40.0%, 55.0% and 74.4% respectively. The positive expression rate of EZH2 in endometrial carcinoma was significantly higher than that of proliferative endometrium, simple endometrial hyperplasia and complex endometrial hyperplasia (P<0.05). In endometrial adenocarcinoma, the expression of EZH2 was closely related with the degree of differentiation. The positive expression rate in pathological grade I cases was was higher than those in grade II and III cases (P<0.05 ).2 The expression of p130 protein in different groupsPositive p130 expression was seen as as brown granules in the nucleus. The positive rate of p130 was 90.0% (18/20) in normal proliferative endometrium, 80.0% (16/20) in simple endometrial hyperplasia, 70.0% (14/20) in complex endomentrial hyperplasia, 55.0% (11/20) in atypical endometrial hyperplasia and 48.8% (21/43) in endometrial adenocarcinoma. The positive rate of the expression of p130 in endometrial carcinoma was significantly lower than that of proliferative endometrium and simple endometrial hyperplasia (P<0.05). The expression of p130 at protein level in endometrial carcinoma was related with histological grade.The expression rate in G2 and G3 endometrial carcinoma cases was lower than that in G1 cases (P<0.05). No relationship was found between the expression of p130 in endometrial carcinoma with other clinical pathology parameters (P>0.05).3 The expression of p16 protein in different groupsThe positive p16 immunohistochemical staining was located in the nucleus and/or cytoplasm of cells as brown granules. From normal proliferative endometrium, simple endometrial hyperplasia, complex endometrial hyperplasia, atypical endometrial hyperplasia to endometrial adenocarcinoma, the expression of p16 was decreased accordingly (90.%, 70.0%, 70.0%, 50.0% and 46.5%, respectively). The positive expression rate of p16 was significantly lower than that in proliferative endometrium (P < 0.05). In endometrial adenocarcinoma, the expression of p16 was correlated with histological grade. The positive expression rate G2 and G3 cases was lower than that in G1 cases(P<0.05). The positive rate of the expression of p16 in cases with lymph node metastasis was lower than that with no lymph node metastasis (P<0.05).4 The relationship among the expressions of EZH2, p130 and p16 in endometrial carcinogenesisAmong the 60 EZH2 positive all different endometrium cases, 30 cases was positive for P130 and 27 cases was positive for P16, while among the 63 EZH2 negative cases, 50 showed P130 positive expression and 49 showed p16 positive expression. The expression of EZH2 was negatively related with that of p130 (P<0.05) and p16 (P<0.05). The expression of p130 and p16 was positively related in endometrial carcinogenesis (P<0.05).Conclusion:1 Expression of EZH2 at the protein level is significantly increased from normal proliferative endometrium, simple endometrial hyperplasia, complex endometrial hyperplasia, atypical endometrial hyperplasia to endometrial adenocarcinoma, while that of p130 and p16 is significantly decreased, suggesting that up-regulated expression of EZH2 and down-regulated expression of p130and p16 may be an important mechanism in the carcinogenesis of endometrial carcinoma.2 The positive expression of EZH2 and p130 was related with histological grade, and the positive expression of p16 was related with histological and lymph node metastasis in endometrial carcinoma. The results indicated that EZH2, p130 and p16 were all involved in the progression of endometrial carcinoma and it may be used as a marker for the jugdement of the biological behavior in endometrial carcinoma.3 The expression of EZH2 was negatively related with that of p130 and p16. The expression of p130 and p16 was positively correlated in endometrial carcinogenesis .