Wu Na-Yiyuan, Huang Hsuan-Shun, Chao Tung Hui, Chou Hsien Ming, Fang Chao, Qin Chong-Zhen, Lin Chueh-Yu, Chu Tang-Yuan, Zhou Hong Hao
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China; Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People's Republic of China; Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, ROC.
Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC.
Cell Rep. 2017 Mar 14;18(11):2557-2565. doi: 10.1016/j.celrep.2017.02.049.
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53 mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.
高级别浆液性卵巢癌（HGSOC）主要起源于输卵管（FT）上皮，且总是携带早期TP53突变。我们之前报道过，由于排卵后FT上皮细胞暴露于活性氧（ROS）和富含血红蛋白的卵泡液（FF）中导致凋亡失败以及DNA双链断裂（DSB）细胞的扩增，肿瘤起始于FT伞端上皮。由于排卵频繁而HGSOC罕见，我们推测黄体期孕酮（P4）可清除p53缺陷的FT细胞。在此我们表明，P4通过P4受体（PRs），通过TNF-α/RIPK1/RIPK3/MLKL途径在Trp53小鼠输卵管上皮和永生化的人p53缺陷的伞端上皮中诱导坏死性凋亡。坏死性凋亡特异性地发生在动情后期，在发情周期的动情前期恢复，并且可以通过补充P4增强。这些结果揭示了孕酮预防卵巢癌这一众所周知能力的机制。
