Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis
Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis
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DOI：
10.1073/pnas.1209171109
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发表时间：
2012-11-06
影响因子：
11.1
通讯作者：
Yazdi, Amir S.
中科院分区：
文献类型：
--
作者：
Drexler, Stefan K.;Bonsignore, Luca;Yazdi, Amir S.
慢性炎症微环境通过尚不完全确定的分子机制促进肿瘤进展。在炎症诱导的皮肤癌中，IL-1受体或caspase-1缺陷小鼠，或骨髓细胞中炎性小体衔接蛋白ASC（包含CARD的骨化相关斑点样蛋白）特异性缺陷小鼠，肿瘤发生率降低，表明IL-1信号传导和炎性小体激活在肿瘤发展中的作用。然而，完全缺乏ASC的小鼠没有受到保护，并且角质形成细胞中特异性缺乏ASC的小鼠比对照组发生更多的肿瘤，这表明与其在骨髓细胞中的促炎作用相反，ASC在角质形成细胞中充当肿瘤抑制剂。因此，ASC蛋白表达在人皮肤鳞状细胞癌中丢失，但在银屑病皮肤病变中没有丢失。用UVB刺激原代小鼠角质形成细胞或人角质形成细胞系HaCaT诱导ASC依赖的p53磷酸化和p53靶基因的表达。在HaCaT细胞中，ASC与p53在UVB照射后在内源性水平上相互作用。因此，不同组织中的ASC可能以相反的方向影响肿瘤生长：它在浸润细胞中具有促炎作用，有利于肿瘤的发展，但它也限制了角质形成细胞对有害刺激的增殖，可能通过p53激活，这有助于抑制肿瘤。
A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor-or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.