Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through beta-catenin.

The hedgehog and Wnt signaling pathways play important roles in human cancers with possible interaction. This study aimed at analysis and correlation of the expression of Gli1, a transcriptional factor and target gene of hedgehog signaling pathway, with clinicopathological parameters and expression of beta-catenin, an important member of the Wnt pathway, in normal, hyperplastic and malignant endometrium. Immunohistochemical study on 15 normal endometrium, 14 simple and complex hyperplasia without atypia, 37 atypical complex hyperplasia and 80 endometrial cancers showed significant Gli1 overexpression and beta-catenin nuclear immunoreactivity in endometrial cancers and atypical endometrial hyperplasia when compared with normal endometrium (P<0.05). Overexpression of Gli1 in endometrial cancers correlated with well-differentiated histological grade (P<0.001), non-myometrial invasion (P=0.004) and superficial myometrial invasion (P=0.041). beta-Catenin nuclear immunoreactivity was also associated with well-differentiated histology (P=0.013). Gli1 overexpression positively correlated with beta-catenin nuclear immunoreactivity in atypical complex hyperplasia (P=0.013) and endometrial carcinoma (P=0.017). Similar Gli1 and beta-catenin protein expression pattern was observed in normal and endometrial cancer cell lines by western blotting. We further showed a complex formation between Gli1 and beta-catenin protein in endometrial cancer cell lines in an immunoprecipitation study. Ectopic overexpression of Gli1 into endometrial cancer cells led to reduced expression of beta-catenin in cell cytoplasm and increased expression of beta-catenin in the nuclei. In summary, overexpression of Gli1 was an early event in endometrial carcinogenesis. Aberrant activation of hedgehog pathway may play important roles in endometrial cancer through beta-catenin nuclear accumulation.