Metaplastic potential of p53 down-regulation in ovarian surface epithelial cells affected by ovulation.
That ovulation is a predisposing factor in common (surface) epithelial ovarian cancer is widely recognized; however, the molecular events which underscore early-stage disease have not been elucidated. In vivo and in vitro studies using an ovine model system were designed to address a premise that oxidative distresses to DNA inflicted upon ovarian surface epithelial cells within a limited diffusion radius of the ovulatory site of follicular rupture, if gone uncorrected by p53-dependent cycle arrest/repair pathways, could yield a progenitor of tumorigenic potential. Immunofluorescence image analysis was used to quantitate the DNA damage marker 8-oxoguanine, the tumor suppressor p53, the base-excision repair polymerase beta, and apoptotic internucleosomal DNA fragmentation in ovarian surface epithelial cells isolated from the perimeter of ovulated follicles. Up-regulation of p53 coincided with accretion of 8-oxoguanine lesions. Oxidative disturbances to DNA were reconciled during the consequent luteal phase (before replicative repair of the ovarian rupture wound). Production of p53 was not related to apoptosis, but rather to induction of polymerase beta. Oxoguanine modifications persisted in cells affected by ovulation in which synthesis of p53 was negated in culture by an antisense oligonucleotide. Inhibition of p53 was associated with discordant cellular growth rates and expression of the cancer antigen CA-125 - a phenotype of metaplastic transformation. It is suggested that the integrity of DNA of ovarian surface epithelial cells is compromised by reactive oxidants and inflammatory mediators generated during the ovulatory process and that malfunction in a damage-recognition and(or) repair mechanism is a determinant in the etiology of ovarian metaplasia and carcinogenesis.
Murdoch
William J
WJ
Reproductive Biology Program, University of Wyoming, Laramie, WY 82071, USA. wmurdoch@uwyo.edu
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D018394:CA-125 Antigen / Q000032:analysis; D002453:Cell Cycle; D002478:Cells, Cultured / Q000187:drug effects; D004249:DNA Damage; D053938:DNA Fragmentation; D019951:DNA Polymerase beta / Q000032:analysis; D004260:DNA Repair; D004847:Epithelial Cells / Q000737:chemistry / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D008183:Luteal Phase; D008679:Metaplasia; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D006080:Ovarian Follicle / Q000473:pathology; D010053:Ovary / Q000473:pathology*; D010060:Ovulation; D010062:Ovulation Induction; D018384:Oxidative Stress; D012422:Rupture, Spontaneous; D012756:Sheep; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D007987:Gonadotropin-Releasing Hormone; C024829:8-hydroxyguanine; D006147:Guanine; D019951:DNA Polymerase beta