title: Mutagenic, surviving and tumorigenic effects of follicular fluid in the context of p53 loss: initiation of fimbria carcinogenesis.
abstract: Ovulation is the strongest risk factor for ovarian high-grade serous carcinoma (HGSC) that largely originates from the fallopian tube fimbriae and always carries loss-of-function mutations of TP53 in both early and late lesions. Mature ovarian follicle contains high level of reactive oxygen species (ROS). When released from ovulation, follicular fluid (FF) bathes the fimbriae and may lead to DNA double-strand break (DSB) and neoplastic transformation. In this study, we examined the mutagenic and tumorigenic activities of human pre-ovulatory FFs. A subset (6/11) of FFs was found with high levels of ROS whereas the antioxidant capacities were indifferent. These ROS(high) FFs induced intracellular ROS and DSBs in the secretory cell population of fimbriae epithelium. When p53 and Rb were turned down, the FF-exposed secretory cells overcame apoptosis and expanded the population carrying ROS and DSB. The cancer initiation and promotion effects of FF were further recapitulated in Trp53 (-/-) mice. When introduced into the mammary fat pad, ROS(high) but not ROS(low) FFs induced early-onset B-cell lymphoma. Cotreatment with physiological concentration of melatonin, a potent antioxidant, ameliorated the mutagenic and tumorigenic effect of ROS(high) FF in vitro and in vivo. The study revealed ROS and mitogens in mature ovarian follicles could initiate the transformation of fimbria epithelium in the context of p53 loss and melatonin is a potent preventive agent.
authors.affiliation: Department of Research, Cervical Cancer Prevention Center.
authors.forename: Hsuan-Shun
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Department of Hematology and Oncology.
authors.forename: Sung-Chao
authors.initials: SC
authors.lastname: Chu
authors.affiliation: Department of Research, Cervical Cancer Prevention Center.
authors.forename: Che-Fang
authors.initials: CF
authors.lastname: Hsu
authors.affiliation: Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hulien 970, Taiwan, Republic of China and.
authors.forename: Pao-Chu
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hulien 970, Taiwan, Republic of China and.
authors.forename: Dah-Ching
authors.initials: DC
authors.lastname: Ding
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, Republic of China.
authors.forename: Meng-Ya
authors.initials: MY
authors.lastname: Chang
authors.affiliation: Department of Research, Cervical Cancer Prevention Center, Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Hulien 970, Taiwan, Republic of China and Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, Republic of China hidrchu@gmail.com.
authors.forename: Tang-Yuan
authors.initials: TY
authors.lastname: Chu
mesh_terms: D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004848:Epithelium / Q000473:pathology; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D015571:Follicular Fluid / Q000502:physiology*; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016296:Mutagenesis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53