Clinical Genomics Unit and Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, 20892, USA; Central Laboratory, Nanshan Hospital, Guangdong Medical College, Shenzhen, Guangdong, 518052, China.
J Pathol. 2014 Feb;232(3):356-68. doi: 10.1002/path.4302.
ΔNp63 is known to be critical in skin development and cancer; however, how it triggers proliferation and inflammation in vivo remains to be elucidated. Here, we find that induced ΔNp63 expression in skin of transgenic mice (TG) results in a hyperproliferative epidermis coupled with inflammatory infiltrates. In situ, infiltrating cells include CD45(+) leukocytes, CD19(+) B lymphocytes, CD3(+) T lymphocytes, CD4(+) T helper, CD25(+)/Foxp3(+) Treg, Ly6B(+) neutrophils, S-100(+) dendritic cells, and macrophages bearing CD11b(+), F4/80(+), CD68(+), and CD206(+) M2 type markers. Transcriptional profiling of TG skin revealed increased gene expression involved in inflammation and immune responses, including Th2/M2 cytokines and chemokines. These genes were co-regulated by ΔNp63 and NF-κB RelA or cRel, and enhanced by TNF-α. Elevated cRel, RelA, and IKKs were observed in TG mouse skin and human squamous carcinomas with ΔNp63 overexpression. Thus, our findings unveil a missing link connecting overexpressed ΔNp63 with aberrant NF-κB activation, pro-inflammatory and type 2 cytokines and chemokines, and host infiltrates during skin inflammation and hyperplasia. Our findings provide a missing link between ΔNp63 overexpression and NF-κB-mediated inflammation, of potential relevance to the pathogenesis of squamous carcinoma.
ΔNp63 已知在皮肤发育和癌症中至关重要；然而，它如何在体内引发增殖和炎症仍有待阐明。在这里，我们发现诱导转基因小鼠（TG）皮肤中 ΔNp63 的表达会导致表皮过度增殖，并伴有炎症浸润。在原位，浸润细胞包括 CD45(+)白细胞、CD19(+)B 淋巴细胞、CD3(+)T 淋巴细胞、CD4(+)辅助 T 细胞、CD25(+)/Foxp3(+)Treg、Ly6B(+)中性粒细胞、S-100(+)树突状细胞和表达 CD11b(+)、F4/80(+)、CD68(+)和 CD206(+)M2 型标志物的巨噬细胞。TG 皮肤的转录谱分析显示，参与炎症和免疫反应的基因表达增加，包括 Th2/M2 细胞因子和趋化因子。这些基因受 ΔNp63 和 NF-κB RelA 或 cRel 的共同调控，并受 TNF-α增强。在 TG 小鼠皮肤和表达 ΔNp63 的人类鳞状细胞癌中观察到 cRel、RelA 和 IKKs 的升高。因此，我们的发现揭示了一个缺失的环节，将过度表达的 ΔNp63 与异常的 NF-κB 激活、促炎和 2 型细胞因子和趋化因子以及宿主浸润联系起来，这些都发生在皮肤炎症和增生过程中。我们的发现提供了 ΔNp63 过表达与 NF-κB 介导的炎症之间缺失的联系，这可能与鳞状细胞癌的发病机制有关。
