Dunfield Lesley D, Dwyer Elizabeth J Campbell, Nachtigal Mark W
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Endocrinology. 2002 Apr;143(4):1174-81. doi: 10.1210/endo.143.4.8733.
Disruptions in TGF beta signaling have been implicated in various human cancers, including ovarian cancer. Our goal was to determine whether ovarian cancer cells isolated from patient ascites fluid were growth inhibited by TGF beta 1 treatment and further characterize the expression and activity profile of TGF beta/Smad signaling components in human ovarian cancer cells. We found that 9 of 10 primary cultures of ovarian cancer cells (OC2-10) were growth inhibited by 16 pM TGF beta 1. One primary ovarian cancer sample (OC1) and the established ovarian cancer cell lines CaOV3 and SkOV3 continued to grow in the presence of TGF beta 1. All cells expressed components of the TGF beta/Smad signaling pathway including TGF beta 1, T beta RI, T beta RII, Smad2, -3, -4, and Smad anchor for receptor activation. Although OC1, CaOV3, and SkOV3 are not growth inhibited by TGF beta 1, they can transmit the TGF beta 1 signal to turn on a transfected TGF beta/Smad reporter gene, p3TP.lux. In addition, all cells up-regulate the endogenous TGF beta target genes Smad7 and PAI-1. p15(Ink4B) mRNA is also up-regulated with TGF beta 1 treatment in OC2-9, whereas the p15(Ink4B) gene has been deleted in OC1, CaOV3, and SkOV3 cells. Homozygous deletion of p15(Ink4B) may account for TGF beta resistance in some populations of ovarian cancer cells. Our data demonstrate that the TGF beta/Smad signaling pathway remains functional in human ovarian cancer cells and suggest that if abnormalities exist in the cellular response of TGF beta signals, they must lie downstream of the Smad proteins.
转化生长因子β（TGFβ）信号通路的紊乱与包括卵巢癌在内的多种人类癌症有关。我们的目标是确定从患者腹水中分离出的卵巢癌细胞是否会受到TGFβ1处理的生长抑制，并进一步表征人类卵巢癌细胞中TGFβ/Smad信号成分的表达和活性谱。我们发现，10个原发性卵巢癌细胞培养物（OC2 - 10）中有9个受到16 pM TGFβ1的生长抑制。一个原发性卵巢癌样本（OC1）以及已建立的卵巢癌细胞系CaOV3和SkOV3在TGFβ1存在的情况下继续生长。所有细胞均表达TGFβ/Smad信号通路的成分，包括TGFβ1、TβRI、TβRII、Smad2、-3、-4以及受体激活的Smad锚定蛋白。尽管OC1、CaOV3和SkOV3不受TGFβ1的生长抑制，但它们可以传递TGFβ1信号以开启转染的TGFβ/Smad报告基因p3TP.lux。此外，所有细胞均上调内源性TGFβ靶基因Smad7和PAI - 1。在OC2 - 9中，p15（Ink4B）mRNA也随着TGFβ1处理而上调，而在OC1、CaOV3和SkOV3细胞中p15（Ink4B）基因已缺失。p15（Ink4B）的纯合缺失可能是某些卵巢癌细胞群体中TGFβ耐药的原因。我们的数据表明，TGFβ/Smad信号通路在人类卵巢癌细胞中仍然具有功能，并表明如果TGFβ信号的细胞反应存在异常，那么这些异常必定位于Smad蛋白的下游。
