Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium.
Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium.
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雌激素暴露的卵巢和输卵管上皮细胞类型特异性遗传毒性
DOI：
10.1186/s12885-020-07524-7
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发表时间：
2020-10-21
期刊：
影响因子：
3.8
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Song L;Tang Z;Peng C;Yang Y;Guo C;Wang D;Guo L;Chen J;Liu C
基因组稳定性的丧失危害基因组稳定性并促进恶性肿瘤。一部分卵巢癌（OvCa）是由DNA修复基因的病理性突变引起的，这些突变导致高度致突变的基因组。然而，为什么卵巢上皮细胞特别容易受到基因组监视系统的故障的影响仍然是一个谜。为了探讨遗传毒性反应的卵巢上皮细胞，定期暴露于高水平的类固醇激素的微环境的独特背景下，我们研究了雌激素诱导的DNA损伤的免疫荧光在OvCa细胞系，动物和人类样本。我们发现OvCa细胞具有高水平的内源性DNA损伤，这与基因组复制无关。损伤负荷的升高可归因于生物活性雌激素而不是其化学模拟衍生物（他莫昔芬）的浓度过高。雌激素对DNA损伤的诱导依赖于激素受体的表达，并发生在细胞周期的G1期和非G1期。此外，同源重组（HR）基因（BRCA 1和BRCA 2）的耗竭加剧了雌激素的遗传毒性，突出了HR抵消雌激素诱导的基因组不稳定性的作用。最后，雌激素诱导的DNA损伤在卵巢和输卵管的上皮细胞中重现。总之，我们的研究揭示了雌激素诱导的遗传毒性和HR缺乏扰乱卵巢和输卵管上皮细胞的基因组稳定性，分别代表微环境和遗传风险因素。补充信息随附于10.1186/s12885-020-07524-7。
Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particularly susceptible to the malfunction of genome surveillance system. To explore the genotoxic responses in the unique context of microenvironment for ovarian epithelium that is periodically exposed to high-level steroid hormones, we examined estrogen-induced DNA damage by immunofluorescence in OvCa cell lines, animal and human samples. We found that OvCa cells are burdened with high levels of endogenous DNA damage that is not correlated with genomic replication. The elevation of damage burden is attributable to the excessive concentration of bioactive estrogen instead of its chemomimetic derivative (tamoxifen). Induction of DNA lesions by estrogen is dependent on the expression of hormone receptors, and occurs in G1 and non-G1 phases of cell cycle. Moreover, depletion of homologous recombination (HR) genes (BRCA1 and BRCA2) exacerbated the genotoxicity of estrogen, highlighting the role of HR to counteract hormone-induced genome instability. Finally, the estrogen-induced DNA damage was reproduced in the epithelial compartments of both ovarian and fallopian tubes. Taken together, our study disclose that estrogen-induced genotoxicity and HR deficiency perturb the genome stability of ovarian and fallopian epithelial cells, representing microenvironmental and genetic risk factors, respectively. Supplementary information accompanies this paper at 10.1186/s12885-020-07524-7.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
14.9
作者：
Ma CJ;Gibb B;Kwon Y;Sung P;Greene EC
通讯作者：
Greene EC
影响因子：
64.8
作者：
Nik-Zainal S;Davies H;Staaf J;Ramakrishna M;Glodzik D;Zou X;Martincorena I;Alexandrov LB;Martin S;Wedge DC;Van Loo P;Ju YS;Smid M;Brinkman AB;Morganella S;Aure MR;Lingjærde OC;Langerød A;Ringnér M;Ahn SM;Boyault S;Brock JE;Broeks A;Butler A;Desmedt C;Dirix L;Dronov S;Fatima A;Foekens JA;Gerstung M;Hooijer GK;Jang SJ;Jones DR;Kim HY;King TA;Krishnamurthy S;Lee HJ;Lee JY;Li Y;McLaren S;Menzies A;Mustonen V;O'Meara S;Pauporté I;Pivot X;Purdie CA;Raine K;Ramakrishnan K;Rodríguez-González FG;Romieu G;Sieuwerts AM;Simpson PT;Shepherd R;Stebbings L;Stefansson OA;Teague J;Tommasi S;Treilleux I;Van den Eynden GG;Vermeulen P;Vincent-Salomon A;Yates L;Caldas C;van't Veer L;Tutt A;Knappskog S;Tan BK;Jonkers J;Borg Å;Ueno NT;Sotiriou C;Viari A;Futreal PA;Campbell PJ;Span PN;Van Laere S;Lakhani SR;Eyfjord JE;Thompson AM;Birney E;Stunnenberg HG;van de Vijver MJ;Martens JW;Børresen-Dale AL;Richardson AL;Kong G;Thomas G;Stratton MR
通讯作者：
Stratton MR
影响因子：
4.1
作者：
Murdoch, WJ;Van Kirk, EA
通讯作者：
Van Kirk, EA
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S