ABSTRACT
The use of Bisphenol S (BPS) was proposed as an alternative to Bisphenol A (BPA), a chemical employed in the production of polycarbonate plastics and epoxy resins. BPA is a xenoestrogen that affects normal physiology in several species. It was reported that BPS may also act as a xenoestrogen with harmful effects in the reproductive system. Here we studied the effects of BPS during the induction of a polycystic ovarian syndrome (PCOS)-like condition in rats. Animals were injected daily with vehicle, DHEA 60â¯mg/kg, BPS 1⯵g/kg and DHEA-BPS, for 20 days. Cell apoptosis, cell proliferation, and EZRIN expression were analyzed by immunohistochemistry. We found an increase in PCNA expression, which correlates with cytoplasmic accumulation of the polarization marker, EZRIN, in the BPS treated groups. Additionally, the administration of BPS in the DHEA treated group augmented the stratification and number of "intraepithelial lumina" in the endometrial surface epithelium.
Subject(s)
Cytoskeletal Proteins/metabolism , Dehydroepiandrosterone/administration & dosage , Endometrium/cytology , Phenols/administration & dosage , Polycystic Ovary Syndrome/metabolism , Sulfones/administration & dosage , Up-Regulation , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Dehydroepiandrosterone/adverse effects , Disease Models, Animal , Endometrium/drug effects , Endometrium/metabolism , Female , Gene Expression Regulation/drug effects , Humans , Organ Size/drug effects , Phenols/adverse effects , Polycystic Ovary Syndrome/chemically induced , Proliferating Cell Nuclear Antigen/metabolism , Rats , Sulfones/adverse effectsABSTRACT
NHERF1 is an adaptor protein expressed in the apical membrane of polarized epithelia, which interacts with the EZRIN-Radixin-Moesin (ERM) family of proteins connecting signaling pathways to the cell cytoskeleton. NHERF1 and EZRIN cooperate in the maintenance of the apical microvilli in polarized epithelial cells. In several types of cancers, NHERF1 and EZRIN are displaced from the apical compartment to the cytoplasm and nuclei of cancer cells. At the present, the distribution of NHERF1 in ovarian tumors is not well known. In this study, NHERF1 expression was examined by immunohistochemistry in cyst adenofibromas, serous borderline tumors, and serous ovarian carcinomas. We observed a strong staining of NHERF1 and EZRIN at the membrane level of borderline tumors and areas of papillary structures in ovarian carcinomas. In tumors without papillary structures and compact structure, NHERF1 was exclusively expressed in the apical pole of the cells at the edges of the clefts of luminal spaces. In contrast, positive expression of EZRIN was found in the membrane of tumor cells within the solid tumor where NHERF1 was not expressed. In summary, this study shows, for the first time, the distribution of NHERF1 in ovarian cancer and reveals a different regulation of NHERF1 and EZRIN expression in ovarian tumors which represents the complexity of the molecular changes of this disease.
Subject(s)
Cell Membrane/metabolism , Cell Polarity/physiology , Cytoskeletal Proteins/metabolism , Ovarian Neoplasms/metabolism , Phosphoproteins/metabolism , Sodium-Hydrogen Exchangers/metabolism , Adult , Cytoskeleton/metabolism , Epithelial Cells/metabolism , Female , Humans , Middle Aged , Morphogenesis/physiology , Protein Transport/physiologyABSTRACT
The aim of the present study was to investigate novel molecular markers that could improve the diagnosis of ovarian cancer patients or be of predictive value. The sequence of the sodium-hydrogen antiporter 3 regulator 1 (SLC9A3R1) gene that codes for the PDZ2 motif of the Na+/H+ exchanger regulatory factor 1 (NHERF1) protein was analyzed. Changes in migration and cell transformation, and alterations of growth factor signaling pathways have been described in cells lacking endogenous NHERF1 or expressing an isoform lacking the function of the PDZ2 domain. Exons 2 and 3, together with flanking intronic sequences of the SLC9A3R1 gene, were amplified and bi-directionally sequenced in 31 primary tumor samples from epithelial ovarian cancer patients. In total, 3 different previously undescribed mutations were detected in 8 out of 31 serous adenocarcinoma tumor samples (25.8%). Bioinformatics analysis predicted a significant effect in the splicing process as a result of the mutations that could disrupt the NHERF1 PDZ2 domain. Point mutations in consensus splicing recognition are a major cause of the splicing defects that are found in several diseases, including cancer. It has previously been shown that a lack of exon 2 and disruption of the PDZ2 domain contribute to cell transformation and leads to modifications in the physiological regulation of the conformational state of NHERF1. Further studies in bigger groups of ovarian cancer patients will determine the importance of this mutation in disease progression and patient survival.
