Wagner M, Kleeff J, Lopez M E, Bockman I, Massaqué J, Korc M
Department of Medicine, University of California, Irvine 92697, USA.
Int J Cancer. 1998 Oct 5;78(2):255-60. doi: 10.1002/(sici)1097-0215(19981005)78:2<255::aid-ijc21>3.0.co;2-8.
Transforming growth factor-beta (TGF-beta) signaling is initiated following heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Both receptors are required for TGF-beta responsiveness. In the present study, we characterized the actions of TGF-beta1 in T3M4 human pancreatic cancer cells, which express low levels of TbetaRI and high levels of TbetaRII. Cells were transiently transfected with p3TP-Lux, a TGF-beta-responsive luciferase reporter gene construct. TGF-beta1 was without effect in parental T3M4 cells, but caused a time- and dose-dependent increase in luciferase activity in T3M4 cells co-transfected with a TbetaRI cDNA expression vector. Co-transfection of TbetaRI with a truncated Smad4 cDNA that is known to block TGF-beta-dependent signaling, abrogated the TbetaRI-induced increase in luciferase activity. Sequencing of the TbetaRI and the Smad4 genes in T3M4 cells did not reveal any mutations. These findings indicate that one mechanism for TGF-beta resistance in pancreatic cancer is due to a quantitative decrease in TbetaRI expression.
转化生长因子-β（TGF-β）信号转导在II型TGF-β受体（TβRII）与I型TGF-β受体（TβRI）异源二聚化后启动。两种受体对于TGF-β反应性都是必需的。在本研究中，我们表征了TGF-β1在T3M4人胰腺癌细胞中的作用，这些细胞表达低水平的TβRI和高水平的TβRII。用p3TP-Lux（一种TGF-β反应性荧光素酶报告基因构建体）对细胞进行瞬时转染。TGF-β1对亲本T3M4细胞没有作用，但在与TβRI cDNA表达载体共转染的T3M4细胞中导致荧光素酶活性呈时间和剂量依赖性增加。将TβRI与已知可阻断TGF-β依赖性信号转导的截短型Smad4 cDNA共转染，消除了TβRI诱导的荧光素酶活性增加。对T3M4细胞中的TβRI和Smad4基因进行测序未发现任何突变。这些发现表明胰腺癌中TGF-β抗性的一种机制是由于TβRI表达的定量减少。
