Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA.
Oncogene. 2010 May 20;29(20):2905-15. doi: 10.1038/onc.2010.64. Epub 2010 Mar 8.
Loss of transforming growth factor-beta receptor III (TbetaRIII) correlates with loss of transforming growth factor-beta (TGF-beta) responsiveness and suggests a role for dysregulated TGF-beta signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TbetaRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TbetaRIII expression in human cells. We localize GATA3's binding to a 10-bp region of the TbetaRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TbetaRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TbetaRIII expression during ccRCC progression.
转化生长因子-β受体 III（TβRIII）的缺失与转化生长因子-β（TGF-β）反应性的丧失相关，提示失调的 TGF-β信号在透明细胞肾细胞癌（ccRCC）进展和转移中起作用。在这里，我们确定在 ccRCC 的所有阶段，TβRIII 在患者匹配的组织样本和细胞系中表达下调。我们发现这种表达的丧失不是由于基因的甲基化，并且我们将 GATA3 定义为第一个在人类细胞中正向调节 TβRIII 表达的转录因子。我们将 GATA3 的结合定位到 TβRIII 近端启动子的 10bp 区域。我们证明 GATA3 mRNA 在 ccRCC 的所有阶段均下调，从机制上表明 GATA3 在 ccRCC 患者的肿瘤组织和细胞系中甲基化，并且抑制正常肾上皮细胞中的 GATA3 表达会下调 TβRIII mRNA 和蛋白表达。这些数据支持一个顺序模型，即通过表观遗传沉默导致 GATA3 表达丧失，从而在 ccRCC 进展过程中降低 TβRIII 表达。
