Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
PLoS One. 2012;7(6):e37697. doi: 10.1371/journal.pone.0037697. Epub 2012 Jun 1.
Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells.
卵泡抑素 (Follistatin, FST) 是一种调节卵泡发生的蛋白，在女性卵巢组织中含量较高。FST 作为 Activin 的拮抗剂，在人类卵巢癌中常升高，因此可能成为治疗卵巢癌的潜在靶点。乳腺癌易感基因 1 (BRCA1) 是人类乳腺癌中已知的肿瘤抑制基因；然而，其在卵巢癌中的作用尚不清楚。我们对稳定过表达野生型 BRCA1 的人卵巢癌细胞系 SKOV3 进行了微阵列分析，并与相应的空载体转染克隆进行了比较。我们发现 BRCA1 的稳定表达不仅刺激 FST 的分泌，同时还抑制 Activin 的表达。为了确定这种现象的生理重要性，我们进一步研究了细胞 BRCA1 对源自正常卵巢或携带 BRCA1 基因突变的卵巢癌患者卵巢的永生化卵巢表面上皮 (IOSE) 细胞中 FST 分泌的影响。在正常 IOSE 细胞中敲低 BRCA1 会导致 FST 分泌下调，同时 Activin 表达上调。此外，与相应的对照相比，IOSE 细胞系和 SKOV3 细胞系中 FST 的敲低导致细胞增殖减少和细胞迁移减少。因此，这些发现表明 BRCA1 作为人类卵巢细胞中 FST 表达和功能的调节剂具有新的功能。
