Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Cancer Res. 2010 Mar 15;70(6):2558-67. doi: 10.1158/0008-5472.CAN-09-2840. Epub 2010 Mar 9.
The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in tumors of different origin, but the molecular bases for STAT3 requirement are only partly understood. To evaluate the contribution of enhanced Stat3 activation in a controlled model system, we generated knock-in mice wherein a mutant constitutively active Stat3C allele replaces the endogenous wild-type allele. Stat3C could enhance the tumorigenic power of the rat Neu oncogene in mouse mammary tumor virus (MMTV)-Neu transgenic mice, triggering the production of earlier onset, more invasive mammary tumors. Tumor-derived cell lines displayed higher migration, invasion, and metastatic ability and showed disrupted distribution of cell-cell junction markers mediated by Stat3-dependent overexpression of the COOH terminal tensin-like (Cten) focal adhesion protein, which was also significantly upregulated in Stat3C mammary tumors. Importantly, the proinflammatory cytokine interleukin-6 could mediate Cten induction in MCF10 cells in an exquisitely Stat3-dependent way, showing that Cten upregulation is a feature of inflammation-activated Stat3. In light of the emerging pivotal role of Stat3 in connecting inflammation and cancer, our identification of Cten as a Stat3-dependent mediator of migration provides important new insights into the oncogenic role of Stat3, particularly in the breast.
转录因子信号转导子和转录激活子 3(STAT3)在不同来源的肿瘤中持续激活,但 STAT3 需求的分子基础仅部分了解。为了在受控模型系统中评估增强的 Stat3 激活的贡献,我们生成了敲入小鼠,其中突变的组成型激活 Stat3C 等位基因取代内源性野生型等位基因。Stat3C 可以增强鼠乳腺肿瘤病毒 (MMTV)-Neu 转基因小鼠中大鼠 Neu 癌基因的致瘤能力,引发更早发生、更具侵袭性的乳腺肿瘤。肿瘤衍生的细胞系表现出更高的迁移、侵袭和转移能力,并显示出细胞-细胞连接标记物的分布中断,这是由 Stat3 依赖性过表达 COOH 末端张力素样 (Cten) 粘着斑蛋白介导的,Cten 在 Stat3C 乳腺肿瘤中也显著上调。重要的是,促炎细胞因子白细胞介素-6 可以以极其依赖 Stat3 的方式在 MCF10 细胞中诱导 Cten 的表达,表明 Cten 的上调是炎症激活 Stat3 的特征。鉴于 Stat3 在连接炎症和癌症方面的新兴关键作用,我们将 Cten 鉴定为 Stat3 依赖性迁移介质,为 Stat3 的致癌作用提供了重要的新见解,特别是在乳腺中。