Transcriptional Up-Regulation of Sox9 by NF-κB in Endometrial Carcinoma Cells, Modulating Cell Proliferation Through Alteration in the p14ARF/p53/p21WAF1 Pathway

Abstract

The Sox factors are a large family of transcription factors that play important roles in tumor development and progression in a variety of human malignancies and diverse developmental processes, but little is known about their roles in endometrial tumorigenesis. Herein, we focus on the functions of Sox9 in endometrial carcinomas. Cells stably overexpressing Sox9 showed a low proliferation rate, particularity in the exponential growth phase, along with increased amounts of p21(WAF1). Transient transfection of Sox9 caused transactivation of p21(WAF1) and p14(ARF) promoters, in cooperation with p53, resulting in activation of the p14(ARF)/p53/p21(WAF1) pathway. Overexpression of p65, and the constitutively active form myristylated Akt, led to an increase in Sox9 expression through transcriptional and posttranslational mechanisms. In normal endometrium, biphasic up-regulation of Sox9 expression was observed during the menstrual cycle, labeling indices being significantly higher in the proliferative stage than in the secretory stage. Moreover, expression also showed a significant stepwise increase from normal through grade 1 to grade 2/3 tumors, being correlated positively with labeling indices of p53, p21(WAF1), pp65, and Ki-67, probably due to a feedback system regarding cell proliferation through NF-κB and Akt signaling. These data, therefore, suggest that associations between Sox9 and NF-κB signaling, as well as Akt status, may participate in modulation of the cell kinetics of endometrial carcinomas cells through alteration in the p14(ARF)/p53/p21(WAF1) pathway.