Investigating the Role of Hepatocyte Nuclear Factor-3 (HNF-3) Alpha and Beta in Prostate Cancer and Cellular Differentiation

摘要

1 Introduction: The Hepatocyte Nuclear Factor-3 (HNF-3) family of forkhead transcription factors (HNF-3 , and ) are essential for endoderm development (Kaestner et al., 1994). HNF-3 proteins, along with other cell specific transcription factors, have been shown to activate the transcription of numerous genes important for hepatocytic and respiratory epithelial cell function (Kaestner et al., 2000). We have recently demonstrated that HNF-3 is a transcriptional potentiator for androgen-regulated prostatic gene expression in epithelial cells and is also necessary for normal murine prostate development (Gao et al., 2003; Mirosevich et al., 2005; Gao et al., 2005). Further, I have obtained significant correlative evidence for the role of HNF-3 and proteins in oncogenic involvement in tumor initiation and/or progression, in addition to prostate epithelial differentiation (Mirosevich et al., In Press). HNF-3 and protein expression is altered in both the LADY transgenic mouse prostate cancer model, in human prostate adenocarcinomas and is differentially expressed in a variety of well established human prostate cancer cell lines (Mirosevich et al., In Press). The precise role that HNF-3 proteins play in normal prostate epithelial cell function, prostate cancer development and progression is unknown. The signal transducer and activator of transcription-3 (Stat3) protein belongs to the Stat family of transcription factors and regulates numerous genes involved in normal cellular processes including cell proliferation, differentiation and apoptosis (Yu & Jove, 2004). In normal cells Stat3 phosphorylation is tightly regulated, however during cellular transformation Stat3 expression becomes altered and is frequently observed to be up-regulated and constitutively activated, i.e. phosphorylated, in many tumors, including prostate carcinomas (Mora et al., 2001).