ERBB2 Is Essential for the Growth of Chemically Induced Skin Tumors in Mice
ERBB2 Is Essential for the Growth of Chemically Induced Skin Tumors in Mice
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DOI：
10.1016/j.jid.2016.11.023
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发表时间：
2017-04-01
影响因子：
6.5
通讯作者：
Schneider, Marlon R.
中科院分区：
文献类型：
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作者：
Dahlhoff, Maik;Muzumdar, Sukalp;Schneider, Marlon R.
尽管表皮生长因子受体在皮肤癌变、炎症和创面愈合中的作用已经确立，但结构上相关的受体ERBB2在该组织中的功能仍未得到充分的研究。为了评估ERBB2在皮肤动态平衡、肿瘤发生和伤口愈合中的作用，我们在小鼠中采用了角蛋白5-定向、cre重组酶介导的ERBB2等位基因打靶。ERBB2(Del)小鼠在角质形成细胞中缺乏ERBB2，没有表现出明显的自发皮肤异常。在创面愈合早期，ERBB2(Del)小鼠创面上皮中角质形成细胞的厚度、数量和增殖率显著降低。与对照小鼠相比，ERBB2del小鼠在应用7，12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate多阶段化学致癌方案后，在更长的时间内保持无乳头状瘤，并显著降低了肿瘤负担。此外，ERBB2(Del)小鼠的肿瘤细胞增殖显著降低，应用12-O-十四烷基佛波酯-13-醋酸酯后，ERBB2的缺失也降低了角质形成细胞的增殖。因此，ERBB2对于表皮及其附属物的发育和动态平衡是必不可少的。然而，在小鼠皮肤化学致癌过程中，ERBB2是皮肤伤口正常愈合和肿瘤进展所必需的，反映了其促进增殖的作用。因此，ERBB2可能是抑制人类非黑色素瘤皮肤癌进展的一个有希望的靶点。
Although the epidermal growth factor receptor has established roles in skin carcinogenesis, inflammation, and wound healing, the functions of the structurally related receptor ERBB2 in this tissue remain poorly explored. To assess the functions of ERBB2 in skin homeostasis, tumorigenesis, and wound healing, we employed keratin 5-directed, cre recombinase-mediated targeting of Erbb2 alleles in mice. Erbb2(del) mice, lacking ERBB2 specifically in keratinocytes, showed no noticeable spontaneous skin abnormalities. During early wound healing, the thickness and the number and proliferation rate of keratinocytes in the wound epithelium of Erbb2(del) mice were significantly reduced. Compared with control littermates, Erbb2 del mice remained free of papillomas for a longer time and had significantly reduced tumor burden after application of the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate multistage chemical carcinogenesis protocol. Furthermore, tumor cell proliferation was substantially reduced in Erbb2(del) mice, and loss of ERBB2 also decreased keratinocyte proliferation after 12-O-tetradecanoylphorbol-13-acetate application. Thus, ERBB2 is dispensable for the development and homeostasis of the epidermis and its appendages. However, reflecting its pro-proliferative role, ERBB2 is required for the normal healing of skin wounds and for the progression of tumors during skin chemical carcinogenesis in mice. Thus, ERBB2 may be a promising target for inhibiting human nonmelanoma skin cancer progression.