Androgens and mesenchymal factors are essential extracellular signals for the development as well as the functional activity of the prostate epithelium. Little is known of the intraepithelial determinants that are involved in prostatic differentiation. Here we found that hepatocyte nuclear factor-3 alpha (HNF-3 alpha), an endoderm developmental factor, is essential for androgen receptor (AR)-mediated prostatic gene activation. Two HNF-3 cis-regulatory elements were identified in the rat probasin (PB) gene promoter, each immediately adjacent to an androgen response element. Remarkably, similar organization of HNF-3 and AR binding sites was observed in the prostate-specific antigen (PSA) gene core enhancer, suggesting a common functional mechanism. Mutations that disrupt these HNF-3 motifs significantly abolished the maximal androgen induction of PB and PSA activities. Overexpressing a mutant HNF-3 alpha deleted in the C-terminal region inhibited the androgen-induced promoter activity in LNCaP cells where endogenous HNF-3 alpha is expressed. Chromatin immunoprecipitation revealed in vivo that the occupancy of HNF-3 alpha on PSA enhancer can occur in an androgen-depleted condition, and before the recruitment of ligand-bound AR. A physical interaction of HNF-3 alpha and AR was detected through immunoprecipitation and confirmed by glutathione-S-transferase pull-down. This interaction is directly mediated through the DNA-binding domain/hinge region of AR and the forkhead domain of HNF-3 alpha. In addition, strong HNF-3 alpha expression, but not HNF-3 beta or HNF-3 gamma, is detected in both human and mouse prostatic epithelial cells where markers (PSA and PB) of differentiation are expressed. Taken together, these data support a model in which regulatory cues from the cell lineage and the extracellular environment coordinately establish the prostatic differentiated response.

Abstract-Preeclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. The differential expression of several microRNAs (miRNAs) has been found in preeclamptic placentas. However, great conflict exists regarding this aspect, and detailed examinations have largely been lacking of miRNA profiles in different parts of the placenta and in maternal plasma of women with this disorder. In this study, a total of 9 downregulated miRNAs (miR-195, miR-223, miR-218, miR-17, miR-18a, miR-19b1, miR-92a1, miR-379, and miR-411) and 7 upregulated miRNAs (miR-210, miR-30a-3p, miR-518b, miR-524, miR-17-3p, miR-151, and miR-193b) were identified in severe preeclampsia (sPE) placentas when compared with normal pregnant controls. In addition, sampling position in the chorionic or basal plate of placenta led to evident variations in differential miRNAs of sPE placentas. In a prospective pregnant cohort, we found that the circulating levels of 3 members of miR-17-92 cluster (ie, miR-18a, miR-19b1, and miR-92a1) were significantly lower, whereas that of miR-210 was higher in sPE patients than those in normal controls at gestational weeks 15 to 18 and at term. The results of in situ hybridization revealed the localization of miR-18a, miR-92a1, and miR-210 in various subtypes of placental trophoblasts and endothelial cells. In human trophoblast cell line, HTR8/SVneo cells, miR-18a could promote trophoblast cell invasion via targeting and suppressing Smad2 expression. This study provides fundamental evidences for exploring the roles of miRNAs in the pathogenesis of preeclampsia. Variations of MicroRNAs in Human Placentas and Plasma From Preeclamptic Pregnancy Xu et al Differential miRNAs in Preeclampsia 1277modulating effect of miR-18a. The data provide important evidences for exploring the pathogenesis of the disease from a noncoding RNA viewpoint. Materials and MethodsAll the details of the materials and methods are provided in the online-only Data Supplement. Study SubjectsIn this study, the collection of human placenta tissues and plasma specimens was performed with the permission of the local ethical committee in the Institute of Zoology, Chinese Academy of Sciences, and informed consent was obtained from all patients enrolled in this study. Placentas and maternal blood samples from normal pregnant and preeclamptic women were obtained from pregnant women who underwent perinatal care in Peking University Third Hospital from August 2010 to October 2012. Totally 20 severe preeclamptic patients who delivered at 35th to 39th weeks and 33 normal pregnant women who delivered at 37th to 39th weeks were enrolled in this study. Their placentas at deliveries and plasma samples at gestational weeks 15 to 18 and weeks 35 to 38 were used. The clinical characteristics of these women are summarized in Table 1. miRNA Microarray AnalysisLarge-scale profiling of miRNA expression was achieved by mammalian miRNA chip array (V2.0, Capitalbio, Beijing, China), which stems from the miRbase release 8.2 (Wellcome Trust Genome Camp...

Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an ''androgen-independent'' stage that results in renewed growth and spread of the cancer. Both nuclear factor-KB (NF-KB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-KB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-KB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-KB signaling in vivo by the absence of the IKBA inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-KB pathway was activated in the ARR 2 PB-myc-PAI (Hi-myc) mouse prostate by crossbreeding into a IKBA +/À haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-KB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-KB pathway may be a potential target for therapy against androgen-independent prostate cancer. [Cancer Res 2008;68(16):6762-9]

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl