Mutagenic, surviving and tumorigenic effects of follicular fluid in the context of p53 loss: initiation of fimbria carcinogenesis
| Autor: | Dah-Ching Ding, Hsuan-Shun Huang, Tang-Yuan Chu, Che-Fang Hsu, Meng-Ya Chang, Sung-Chao Chu, Pao-Chu Chen |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Cancer Research medicine.medical_specialty Carcinogenesis Cell Survival media_common.quotation_subject Fimbria Population Context (language use) Biology medicine.disease_cause Epithelium Internal medicine Tumor Cells Cultured medicine Animals Humans DNA Breaks Double-Stranded Neoplastic transformation Neoplasms Glandular and Epithelial education Ovulation Fallopian Tubes media_common Mice Knockout Ovarian Neoplasms education.field_of_study General Medicine Middle Aged Follicular fluid Follicular Fluid Mice Inbred C57BL Endocrinology Mutagenesis Apoptosis Cancer research Female Tumor Suppressor Protein p53 Reactive Oxygen Species |
| Zdroj: | Carcinogenesis. 36:1419-1428 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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