Immunomodulatory role of Keratin 76 in oral and gastric cancer.
Immunomodulatory role of Keratin 76 in oral and gastric cancer.
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DOI：
10.1038/s41467-018-05872-4
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发表时间：
2018-08-24
影响因子：
16.6
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Sequeira I;Neves JF;Carrero D;Peng Q;Palasz N;Liakath-Ali K;Lord GM;Morgan PR;Lombardi G;Watt FM
角蛋白76(Krt76)表达于皮肤、口腔和胃鳞状细胞的分化上皮层。Krt76在口腔鳞状细胞癌(OSCC)中表达下调与预后不良相关。我们发现，Krt76基因在小鼠身上的基因消融会导致小鼠脾和淋巴结增大，调节性T细胞(Tregs)增加，促炎细胞因子水平升高。Krt76CD73树突状细胞的抑制能力增强，−/−表达增加，而其效应T细胞的增殖能力低于对照组。Krt76的缺失会增加舌头和鳞状胃中致癌物质诱发的肿瘤。当Treg水平在实验中升高时，癌症的发生进一步增加。致癌反应包括促炎细胞因子的上调和肿瘤微环境中Tregs的增加。Tregs也在人类口腔鳞状细胞癌中积累，表现为Krt76丢失。我们的研究强调了上皮细胞通过与免疫系统的细胞沟通来调节癌症发生的作用。角蛋白76(Krt76)是一种上皮分化标志物，在口腔鳞状细胞癌中表达下调，与预后不良相关。在这里，作者表明，在小鼠模型中，Krt76的遗传消融通过增强Tregs的积累而导致癌症易感性的增加。
Keratin 76 (Krt76) is expressed in the differentiated epithelial layers of skin, oral cavity and squamous stomach. Krt76 downregulation in human oral squamous cell carcinomas (OSCC) correlates with poor prognosis. We show that genetic ablation of Krt76 in mice leads to spleen and lymph node enlargement, an increase in regulatory T cells (Tregs) and high levels of pro-inflammatory cytokines. Krt76−/− Tregs have increased suppressive ability correlated with increased CD39 and CD73 expression, while their effector T cells are less proliferative than controls. Loss of Krt76 increases carcinogen-induced tumours in tongue and squamous stomach. Carcinogenesis is further increased when Treg levels are elevated experimentally. The carcinogenesis response includes upregulation of pro-inflammatory cytokines and enhanced accumulation of Tregs in the tumour microenvironment. Tregs also accumulate in human OSCC exhibiting Krt76 loss. Our study highlights the role of epithelial cells in modulating carcinogenesis via communication with cells of the immune system. Keratin 76 (Krt76) is an epithelial differentiation marker that is downregulated in oral squamous cell carcinomas, correlating with poor prognosis. Here the authors show that genetic ablation of Krt76 in a mouse model results in increased susceptibility to carcinogenesis via enhanced accumulation of Tregs.