Hempel Nadine, How Tam, Dong Mei, Murphy Susan K, Fields Timothy A, Blobe Gerard C
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cancer Res. 2007 Jun 1;67(11):5231-8. doi: 10.1158/0008-5472.CAN-07-0035. Epub 2007 May 23.
The transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta, activin, and inhibin, all have prominent roles in regulating normal ovarian function. Betaglycan, or the type III TGF-beta receptor, is a coreceptor that regulates TGF-beta, activin, and inhibin signaling. Here, we show that betaglycan expression is frequently decreased or lost in epithelial derived ovarian cancer at both the mRNA and protein level, with the degree of loss correlating with tumor grade. Treatment of ovarian cancer cell lines with the methyltransferase inhibitor 5-aza-2-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in significant synergistic induction of betaglycan message levels and increased betaglycan protein expression, indicating that epigenetic silencing may play a role in the loss of betaglycan expression observed in ovarian cancer. Although restoring betaglycan expression in Ovca429 ovarian cancer cells is not sufficient to restore TGF-beta-mediated inhibition of proliferation, betaglycan significantly inhibits ovarian cancer cell motility and invasiveness. Furthermore, betaglycan specifically enhances the antimigratory effects of inhibin and the ability of inhibin to repress matrix metalloproteinase levels in these cells. These results show, for the first time, epigenetic regulation of betaglycan expression in ovarian cancer, and a novel role for betaglycan in regulating ovarian cancer motility and invasiveness.
转化生长因子-β（TGF-β）超家族成员，即TGF-β、激活素和抑制素，在调节正常卵巢功能方面均发挥着重要作用。β聚糖，即III型TGF-β受体，是一种调节TGF-β、激活素和抑制素信号传导的共受体。在此，我们发现β聚糖在卵巢上皮源性癌中的表达在mRNA和蛋白质水平上经常降低或缺失，其缺失程度与肿瘤分级相关。用甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷和组蛋白脱乙酰酶抑制剂曲古抑菌素A处理卵巢癌细胞系，可显著协同诱导β聚糖的信使水平并增加β聚糖蛋白表达，这表明表观遗传沉默可能在卵巢癌中观察到的β聚糖表达缺失中发挥作用。尽管在Ovca429卵巢癌细胞中恢复β聚糖表达不足以恢复TGF-β介导的增殖抑制，但β聚糖可显著抑制卵巢癌细胞的运动性和侵袭性。此外，β聚糖可特异性增强抑制素的抗迁移作用以及抑制素在这些细胞中抑制基质金属蛋白酶水平的能力。这些结果首次表明了卵巢癌中β聚糖表达的表观遗传调控，以及β聚糖在调节卵巢癌运动性和侵袭性方面的新作用。
