Han S-U, Kwak T-H, Her K H, Cho Y-H, Choi C, Lee H-J, Hong S, Park Y S, Kim Y-S, Kim T-A, Kim S-J
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Oncogene. 2008 Jan 24;27(5):675-83. doi: 10.1038/sj.onc.1210686. Epub 2007 Jul 23.
The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-beta (TGF-beta) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-beta-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-beta signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-beta signaling pathway. In nine human gastric cancer cell lines examined, TGF-beta-responsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-beta signaling in CEA expression, we selected two TGF-beta unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-beta type II receptor and SNU484 cells that express low to undetectable level of the TGF-beta pathway intermediate protein, Smad3. Restoration of TGF-beta signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
癌胚抗原（CEA）家族由一大组在进化和结构上存在差异的糖蛋白组成。转化生长因子-β（TGF-β）信号通路与TGF-β敏感结肠细胞中CEA分泌的刺激有关，从而可能调节细胞黏附和分化。然而，TGF-β信号通路靶向的特定CEA或CEA表达的潜在机制尚未阐明。在本研究中，我们调查了TGF-β信号通路靶向的特定CEA。在所检测的9种人胃癌细胞系中，对TGF-β有反应的细胞系显示CEA呈阳性表达。这些细胞系中CEA蛋白的表达模式与CEA（CEACAM5）和CEACAM6转录本的水平密切相关，但并非所有这些细胞中都观察到CEACAM1的表达。为了研究TGF-β信号通路在CEA表达中的作用，我们选择了两种对TGF-β无反应的胃癌细胞系；一种是TGF-β II型受体发生突变的SNU638细胞，另一种是TGF-β通路中间蛋白Smad3表达水平低至无法检测的SNU484细胞。这些细胞中TGF-β信号通路的恢复诱导了CEA的表达，并增加了CEA（CEACAM5）和CEACAM6启动子的活性。在野生型小鼠胃上皮中观察到CEA表达，但在Smad3基因敲除小鼠中明显降低。这些发现表明CEA（CEACAM5）和CEACAM6是Smad3介导的TGF-β信号通路的主要靶基因。
