Subject(s)
Douglas' Pouch/pathology , Endometriosis/diagnosis , Adult , Endometriosis/pathology , Female , HumansABSTRACT
The role of RNA-binding proteins in cancer biology is recognized increasingly. The nucleocytoplasmic shuttling and AU-rich RNA-binding protein HuR stabilizes several cancer-related target mRNAs. The proto-oncogene c-fms, whose 3'untranslated region (3'UTR) is not AU-rich, is associated with poor prognosis in breast cancer. Using a large breast-cancer tissue array (N=670), we found nuclear HuR expression to be associated with nodal metastasis and independently with poor survival (P=0.03, RR 1.45), as well as to be co-expressed with c-fms in the breast tumors (P=0.0007). We described c-fms mRNA as a direct target of HuR in vivo, and that HuR bound specifically to a 69-nt region containing 'CUU' motifs in 3'UTR c-fms RNA. Overexpressing or silencing HuR significantly up- or down-regulated c-fms RNA expression, respectively. We also found that known glucocorticoid stimulation of c-fms RNA and protein is largely dependent on the presence of HuR. HuR, by binding to the 69-nt wild type, but not mutant, c-fms sequence can regulate reporter gene expression post-transcriptionally. We are the first to describe that HuR can regulate gene expression by binding non-AU-rich sequences in 3'UTR c-fms RNA. Collectively, our findings suggest that HuR plays a supportive role for c-fms in breast cancer progression by binding a 69-nt element in its 3'UTR, thus regulating its expression.
Subject(s)
Antigens, Surface/physiology , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic/physiology , Genes, fms , RNA-Binding Proteins/physiology , 3' Untranslated Regions , Base Sequence , Cohort Studies , Down-Regulation , ELAV Proteins , ELAV-Like Protein 1 , Humans , Immunohistochemistry , Proto-Oncogene Mas , RNA, Messenger/genetics , Survival AnalysisABSTRACT
The aim of the study was to evaluate the immunohistochemical expression of cell proliferation and apoptosis markers in the ovaries and uterus of tamoxifen-treated rats. Twelve rats (150-200 g) were divided into two equal groups. The study group received daily intraperitoneal injections of tamoxifen dissolved in 5% dimethyl sulfoxide (n= 6). The control group received only the vehicle (n= 6). The rats were sacrificed at the 20th day of injection and were perfused. The ovaries and uterus of the rats were extracted. The sections were immunohistochemically stained with cell proliferation marker Ki-67 and the apoptosis markers PTEN and CD95. The expressions of the markers were quantified by a semiquantitative H-score method in myometrium, endometrial glands, ovarian surface epithelium, ovarian follicles, corpus luteum, and ovarian stroma separately. The mean H-scores of CD95 and PTEN obtained from myometrium, glandular endometrium, ovarian surface epithelium, ovarian follicles, corpus luteum, and ovarian stroma did not show significant difference between the study and the control groups. Proliferative index (Ki-67) of endometrial glands was significantly higher in the study group than in the control group (P < 0.05). In addition, proliferative index (Ki-67) of corpus luteum was significantly higher in the study group than in the control group (P < 0.05). Tamoxifen treatment has a potential to stimulate the cell proliferation of endometrial glands and corpus luteum in tamoxifen-treated rats. Apoptosis markers of PTEN and CD95 did not demonstrate significant difference after the tamoxifen treatment.
