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一种将小窝蛋白-1下调与浆液性上皮性卵巢癌细胞中BRCA1功能障碍联系起来的新途径。

A Novel Pathway that Links Caveolin-1 Down-Regulation to BRCA1 Dysfunction in Serous Epithelial Ovarian Cancer Cells.

作者信息

Xu Jingyao, Agyemang Stephanie, Qin Yunlong, Aysola Kartik, Giles Mercedes, Oprea Gabriela, O'Regan Ruth M, Partridge Edward E, Harris-Hooker Sandra, Rice Valarie Montgomery, Reddy E Shyam P, Rao Veena N

机构信息

Cancer Biology Program, Department of OB/GYN, Georgia Cancer Center for Excellence, Grady Health System, Atlanta, GA 30303, USA.

Emory University School of Medicine, Atlanta, GA, USA.

出版信息

Enliven Chall Cancer Detect Ther. 2014;1(1). doi: 10.18650/2376-046x.11004.

DOI:10.18650/2376-046x.11004
PMID:25594072
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4292936/
Abstract

Ovarian cancer is the second most common gynecological cancer and the five-year survival rate is only about 40%. High-grade serous carcinoma is the pre-dominant histotype associated with hereditary ovarian cancer and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. BRCA1 and its isoform BRCA1a are multifunctional proteins that are the most evolutionary conserved of all the other splice variants. Our group has previously reported that BRCA1/1a proteins, unlike K109R and C61G mutants, suppress growth of ovarian cancer cells by tethering Ubc9. In this study we found wild type BRCA1/1a proteins to induce expression of caveolin-1, a tumor suppressor in BRCA1-mutant serous epithelial ovarian cancer (SEOC) cells by immunofluorescence analysis. The K109R and C61G disease associated mutant BRCA1 proteins that do not bind Ubc9 were not as efficient in up-regulation of caveolin-1 expression in SEOC cells. Additionally, immunofluorescence analysis showed BRCA1/1a proteins to induce redistribution of Caveolin-1 from cytoplasm and nucleus to the cell membrane. This is the first study demonstrating the physiological link between loss of Ubc9 binding, loss of growth suppression and loss of Caveolin-1 induction of disease-associated mutant BRCA1 proteins in SEOC cells. Decreased Caveolin-1 expression combined with elevated Ubc9 expression can in the future be used as an early biomarker for BRCA1 mutant SEOC.

摘要

卵巢癌是第二常见的妇科癌症，其五年生存率仅约为40%。高级别浆液性癌是与遗传性卵巢癌相关的主要组织学类型，携带BRCA1基因遗传突变的女性终生患病风险为40%-60%。BRCA1及其异构体BRCA1a是多功能蛋白，是所有其他剪接变体中进化上最保守的。我们团队此前曾报道，与K109R和C61G突变体不同，BRCA1/1a蛋白通过与Ubc9结合来抑制卵巢癌细胞的生长。在本研究中，我们通过免疫荧光分析发现野生型BRCA1/1a蛋白可诱导小窝蛋白-1的表达，小窝蛋白-1是BRCA1突变的浆液性上皮性卵巢癌（SEOC）细胞中的一种肿瘤抑制因子。不与Ubc9结合的K109R和C61G疾病相关突变型BRCA1蛋白在SEOC细胞中上调小窝蛋白-1表达方面效率较低。此外，免疫荧光分析显示BRCA1/1a蛋白可诱导小窝蛋白-1从细胞质和细胞核重新分布到细胞膜。这是第一项证明SEOC细胞中与疾病相关的突变型BRCA1蛋白失去Ubc9结合、失去生长抑制以及失去小窝蛋白-1诱导之间存在生理联系的研究。未来，小窝蛋白-1表达降低与Ubc9表达升高相结合可作为BRCA1突变型SEOC的早期生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/b71fb610386e/nihms639537f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/d00b1f79ddd4/nihms639537f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/c648ef7935fd/nihms639537f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/e57e53c2b0b3/nihms639537f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/b71fb610386e/nihms639537f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/d00b1f79ddd4/nihms639537f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/c648ef7935fd/nihms639537f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/e57e53c2b0b3/nihms639537f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/feae/4292936/b71fb610386e/nihms639537f4.jpg

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本文引用的文献

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BRCA and Early Events in the Development of Serous Ovarian Cancer.BRCA与浆液性卵巢癌发生中的早期事件
将BRCA1功能障碍与具有腹膜通透性和腹水的高级别浆液性上皮性卵巢癌相联系的分子机制
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