IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation
IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation
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DOI：
10.1016/j.ebiom.2019.01.061
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Chu, Tang-Yuan
中科院分区：
文献类型：
--
作者：
Hsu, Che-Fang;Huang, Hsuan-Shun;Chu, Tang-Yuan
背景资料：输卵管伞被认为是卵巢高级别浆液性癌的主要起源组织，持续排卵是卵巢高级别浆液性癌的主要危险因素。以前，我们发现了人排卵卵泡液（FF）注射到Trp 53-null小鼠的乳腺脂肪垫后的肿瘤发生活性。我们还发现了FF-ROS的诱变活性和Hb从逆行月经中的促排卵拯救活性。方法：从两组IVF患者的排卵性FF中，鉴定出负责人菌毛上皮细胞转化的主要生长因子。激活的机制，生长因子的信号转导途径，以及恶性转化的细胞和遗传表型的characteristic.Findings：在这项研究中，我们发现，胰岛素样生长因子（IGF）轴蛋白，包括IGFBP结合的IGF 2以及IGFBP裂解酶PAPP-A，大量存在于FF。在与菌毛上皮细胞膜上的糖胺聚糖接合后，PAPP-A切割IGFBPs并释放IGF 2以与IGF 1 R结合。通过IGF-1 R/AKT/mTOR和IGF-1 R/AKT/NANOG途径，FF-IGF导致干性和存活，并且在TP 53/Rb或TP 53/CCNE 1缺失的情况下，导致菌毛上皮细胞的克隆扩增和恶性转化。通过从FF中耗尽每个IGF轴组分，我们证明IGF 2、IGFBP 2/6和PAPP-A都是必需的，并赋予大部分转化和再生活性。释义：这项研究揭示了FF-IGF轴的功能是在排卵后再生组织损伤，并促进由p53和Rb通路中断启动的菌毛上皮细胞的转化。（MOST 106-2314-B303- 001-MY 2; MOST 105-2314-B-303-017-MY 2; MOST 107-2314-B-303-013-MY 3）和台湾佛教慈济总医院（TCMMP 104 -04-01）。(c)2019作者（S）由Elsevier B. V.发布。这是CC BY-NC-ND许可下的开放获取文章（http：//creativecommons. org/许可证/by-nc-nd/4.0/）。
Background: The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF.Methods: From two cohorts of ovulatory FF retrieved fromIVF patients, themain growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized.Findings: In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities. Interpretation: This study revealed that the FF-IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53-and Rb-pathway disruptions.Fund: The study was supported by grants of theMinistry of Science and Technology, Taiwan (MOST 106-2314-B303- 001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01). (c) 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).