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

Enliven. Challenges in cancer detection and therapy Pub Date : 2014-01-01 DOI:10.18650/2376-046x.11004

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

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引用次数: 10

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.

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浆液性上皮性卵巢癌细胞中Caveolin-1下调与BRCA1功能障碍的新途径

卵巢癌是第二常见的妇科癌症，5年生存率只有40%左右。高级别浆液性癌是与遗传性卵巢癌相关的前显性组织型，携带BRCA1基因遗传突变的女性的终生风险为40-60%。BRCA1及其同种异构体BRCA1a是多功能蛋白，是所有其他剪接变体中最具进化保守性的。本课题组此前报道，与K109R和C61G突变体不同，BRCA1/1a蛋白通过捆绑Ubc9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蛋白可诱导肿瘤抑制因子caveolin-1在brca1突变型浆液上皮性卵巢癌(SEOC)细胞中的表达。不结合Ubc9的K109R和C61G疾病相关突变BRCA1蛋白在SEOC细胞中上调小窝蛋白-1表达的效率不高。此外，免疫荧光分析显示BRCA1/1a蛋白诱导Caveolin-1从细胞质和细胞核重新分布到细胞膜。这是首次证明SEOC细胞中Ubc9结合缺失、生长抑制缺失和疾病相关突变BRCA1蛋白Caveolin-1诱导缺失之间存在生理联系的研究。Caveolin-1表达的降低与Ubc9表达的升高可以在未来作为BRCA1突变体SEOC的早期生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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