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组成性激活的 Stat3 通过上调 Cten 增强了乳腺肿瘤中的神经介导的迁移和转移。

Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten.

机构信息

Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.

出版信息

Cancer Res. 2010 Mar 15;70(6):2558-67. doi: 10.1158/0008-5472.CAN-09-2840. Epub 2010 Mar 9.

Abstract

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.

摘要

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。

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