Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation
Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation
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DOI：
10.1172/jci38854
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发表时间：
2009-11-01
影响因子：
15.9
通讯作者：
Wang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Bornstein, Sophia;White, Ruth;Wang, Xiao-Jing
SMAD4是TGF-β信号传导的中心介体，其表达在几种癌症类型的恶性阶段被下调或丢失。在这项研究中，我们发现SMAD4不仅在人头和颈部鳞状细胞癌（HNSCC）恶性病变中经常被下调，而且在严重正常的邻近颊粘膜中也被下调。为了深入了解这种观察的重要性，我们产生了在头部和颈上皮中删除SMAD4的小鼠（此处称为HN-SMAD4（ - / - ）小鼠），发现它们开发了自发的HNSCC。有趣的是，来自HN-SMAD4（ - / - ）小鼠的正常头部和颈部组织和HNSCC均表现出增加的基因组不稳定性，这与编码Fanconi贫血/BRCA（FANC/BRCA）DNA修复途径的基因的下调表达和功能相关与HNSCC在人类中的敏感性有关。与此一致，进一步的分析表明，SMAD4蛋白的下调与人HNSCC中BrICA1和RAD51蛋白的下调之间存在相关性。除了上述肿瘤上皮的变化外，HN-SMAD4（ - / - ）小鼠的正常头部和颈部组织和HNSCC都表现出严重的炎症，这与TGF-beta 1的表达增加并激活了SMAD3。我们介绍了我们认为是HNSCC的第一个单个基因敲除模型，其中HNSCC形成和入侵都是由于SMAD4缺失而发生的。我们的结果揭示了SMAD4与FANC/BRCA途径之间的有趣联系，并突出了上皮SMAD4损失对炎症的影响。
Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4(-/-) mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4(-/-) mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brica1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4(-/-) mice exhibited severe inflammation, which was associated with increased expression of TGF-beta 1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.