Expression And Clinical Significance Of Beclin1 And PTEN In Endometrial Carcinoma

Background: Endometrial carcinoma is one of the most common malignant neoplasms in the female reproductive system. The incidence rate of endometrial carcinoma increases, but its pathogenesis is still unclear. Tumor suppressor gene inactivation and oncogene activation may play an important role in its carcinogenesis and progression.Beclinl (BECN1) is a tumor suppressor gene related to autophagy. It localizes to chromosome 17q21, which is usually absent in ovarian, breast and prostate cancers. According to recent reports, the presence of BECN1 allelic deletion can attenuate the autoghagic activity and contribute to cancer development. Another tumor suppressor gene PTEN was found in 1997. PTEN is mutated and inactivated in many malignant tumors, and the mutation rate about 33%-55% in endometrial carcinoma is the highest. Among all the known genes that are related to the carcinogenesis and progression of endometrial carcinoma, such as p53, KRAS and β -catenin, the mutation rate of PTEN is the highest. Recently, many researches indicated that mutation and inactivation of PTEN was closely correlated to endometrial carcinoma.Many studies showed that BECN1 and PTEN might affect the carcinogenesis and tumor progression through co-participating in the regulation of autophagic activity. The inhibition of autophagic capacity can promote preneoplastic cell to develop. The type I and III PI3-kinases (I PI3K and III PI3K) are involved in autophagy signal regulation. Type IPI3K and its downstream signal transduction components, Akt and TOR pathway, have been implicated in autophagy suppression, while PTEN is a negative regulator of I PI3K and acts as an activator of autoghagy. In contrast, III PI3K has been proved to be required for both autophagic vesicle formation and vesicular transportation to the lysosome. BECN1 binds to III PI3K and forms III PI3K/BECN1 complex that regulates other Apg proteins' localization to autophagosome and induces autophagy. It is thus clear that BECN1 and PTEN may affect the regulation of autophagy together. However, no report on BECN1 expression in endometrial carcinoma has been found, and there is no report on the correlation of BECN1 and PTEN in the regulation of autophagy in the carcinogenesis and progression of endometrial carcinoma.Objective: Our aim is to investigate the roles of protein BECN1 and PTEN and analyze their correlation in the carcinogenesis and progression of the endometrial carcinoma. At the same time, it is analyzed that the relationship between the expression of BECN1 and PTEN and clinicopathologic features, such as pathologic stage, histological type, cell differentiation and myometrial invasion to elucidate the clinical significance of these two proteins in endometrial carcinoma.Materials and Methods: 1. A total of 128 specimens of hysterectomia tissue were collected. Specimens of endometrial carcinoma were obtained from 79 patients with a median age of 57 (range 35-82 years), and specimens of endometrial hyperplasia were obtained from 34 patients with a median age of 45 (range 34-74 years), and specimens of normal proliferative endometrium were obtained from 15 patients that had been hysterectomized because of hysteromyoma with a median age of 46 (range 39-56 years). 2. The clinicopathologic features of all endometrial carcinoma, including age, stage, histological type, cell differentiation, myometrial invasion and cervical invasionwere recorded. 3. The expression of BECNl and PTEN in endometrial carcinoma, endometrial hyperplasia and normal endometrium was assayed by immunohistochemistry with a semiquantitative method. The relationship between the expression of BECNl and PTEN with the clinical pathologic features of endometrial carcinoma was analyzed. 4. All data were processed with SPSS 10.0 for windows.Results 1. Expression of BECNl protein: BECNl expression fell off fromnormal endometrium, endometrial hyperplasia to endometrial carcinoma (/v2=42.318,P=0.000). BECNl negative rate was significantly lower in normal endometrium than in endometrial hyperplasia and endometrial carcinoma tissues, respectively. 2. Relationship between BECNl and clinicopathologic parameters: BECNl expression was associated with histological type (P=0.010) and cell differentiation (P=0.032), but not with age (P=0.301), pathologic stage (P=0.889), myometrial invasion (P=0.495) and cervical invasion (P=0.321). 3. Expression of PTEN protein and its relationship with clinicopathologic parameters: PTEN expression fell off from normal endometrium,endometrial hyperplasia to endometrial carcinoma (^2=31.746, P=0.000). It wasassociated with histological type (P=0.048), cell differentiation (P=0.024) and myometrial invasion (P=0.029), but not with age (P=0.379), pathologic stage (P=0.263), and cervical invasion (P=0.373). 4. Correlation between BECNl and PTEN: BECNl expression had a positive correlation with PTEN in 79 specimens of endometrial carcinoma (r=0.816, P==0.000).Conclusions: 1. The expression of BECNl and PTEN fell off from normal endometrium, endometrial hyperplasia to endometrial carcinoma, which suggested that BECNl and PTEN might play a role in the development of endometrioid adenocarcinoma. 2. BECNl expression was associated with histological type and cell differentiation, suggesting that loss of BECNl protein may predict poor prognosis. 3. The expression of PTEN was related to histological type, cell differentiation and myometrial invasion, suggesting that PTEN expression may be a prognosis factor. 4. A positive correlation between the expression of BECNl and PTEN suggests that BECNland PTEN may have co-effects on the carcinogenesis and progression of endometrialcarcinoma, especially in endometrioid adenocarcinoma.