Schwarte-Waldhoff I, Klein S, Blass-Kampmann S, Hintelmann A, Eilert C, Dreschers S, Kalthoff H, Hahn S A, Schmiegel W
Medizinische Universitätsklinik, Knappschaftskrankenhaus, Ruhr-Universität Bochum, Germany.
Oncogene. 1999 May 20;18(20):3152-8. doi: 10.1038/sj.onc.1202641.
We recently identified DPC4/Smad4 as a candidate tumor suppressor gene mutated or lost in one half of pancreatic carcinomas and in a subset of colon and biliary tract carcinomas. DPC4 plays a key role in signal transduction of the TGF-beta superfamily of molecules and inactivation of TGF-beta mediated growth inhibition is supposed to be the driving force for DPC4 inactivation in human tumors. However, DPC4 mediated tumor suppression by reconstitution of defective cells has not yet been reported. Here we show suppression of tumorigenicity in nude mice by stable reexpression of DPC4 in SW480 colon carcinoma cells. In vitro growth of DPC4-transfected cells was not affected and resistance towards TGF-beta mediated growth inhibition was retained. Instead, cells exhibited morphological alterations and adhesion and spreading were accelerated. These phenotypic changes were associated with reduced expression levels of the endogenous urokinase-type plasminogen activator (uPA) and plasminogen-activator-inhibitor-1 (PAI-1) genes, the products of which are implicated in the control of cell adhesion and invasion. In patients, high expression levels of uPA and PAI-1 correlate with poor prognosis. Thus, reduced expression of uPA and PAI-1 is consistent with suppression of tumorigenicity in DPC4 reconstituted cells. These results demonstrate DPC4's tumor suppressive function and suggest a potential role for DPC4 as a modulator of cell adhesion and invasion.
我们最近鉴定出DPC4/Smad4是一种候选肿瘤抑制基因，在一半的胰腺癌以及一部分结肠癌和胆管癌中发生突变或缺失。DPC4在TGF-β超家族分子的信号转导中起关键作用，并且TGF-β介导的生长抑制失活被认为是人类肿瘤中DPC4失活的驱动力。然而，通过重建缺陷细胞来实现DPC4介导的肿瘤抑制作用尚未见报道。在此我们展示了通过在SW480结肠癌细胞中稳定重新表达DPC4，可抑制裸鼠的肿瘤发生。DPC4转染细胞的体外生长未受影响，并且对TGF-β介导的生长抑制的抗性得以保留。相反，细胞表现出形态改变，并且黏附与铺展加速。这些表型变化与内源性尿激酶型纤溶酶原激活剂（uPA）和纤溶酶原激活剂抑制剂-1（PAI-1）基因的表达水平降低相关，其产物参与细胞黏附和侵袭的调控。在患者中，uPA和PAI-1的高表达与预后不良相关。因此，uPA和PAI-1表达降低与DPC4重建细胞中肿瘤发生的抑制一致。这些结果证明了DPC4的肿瘤抑制功能，并提示DPC4作为细胞黏附和侵袭调节剂的潜在作用。
