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首页> 外文期刊>Nature >Opposing roles for calcineurin and ATF3 in squamous skin cancer
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Opposing roles for calcineurin and ATF3 in squamous skin cancer

机译：钙调神经磷酸酶和ATF3在鳞状皮肤癌中的相反作用

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Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurinuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xeno-grafts, in immune compromised mice, of H-ras~(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.
机译：钙调神经磷酸酶抑制剂（例如环孢菌素A（CsA））是器官移植接受者免疫抑制治疗的主要手段。皮肤鳞状细胞癌（SCC）是使用这些药物治疗的主要并发症，其风险比正常人群高65至100倍。相比之下，基底细胞癌（BCC），皮肤的另一种主要的角质形成细胞衍生的肿瘤，黑素瘤和内部恶性肿瘤的发生率则显着降低。在这里我们报告遗传和药理学抑制钙调神经磷酸酶/激活的T细胞（NFAT）功能的核因子促进小鼠皮肤和异种移植，免疫受损的小鼠中H-ras〜（V12）的肿瘤形成（也称为表达Hras1）的原代人角质形成细胞或角质形成细胞衍生的SCC细胞。钙调神经磷酸酶/ NFAT抑制作用抵消了p53（也称为TRP53）依赖性癌细胞的衰老，从而增加了致瘤潜力。在实验条件下和临床肿瘤中，钙调神经磷酸酶/ NFAT抑制作用选择性诱导ATF3（“扩大的” AP-1家族的成员），而增加的ATF3表达可抑制p53依赖性衰老并增强致癌潜力。因此，完整的钙调神经磷酸酶/ NFAT信号是p53和衰老相关机制（防止皮肤鳞状癌发展）的关键条件。

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  • 来源
    《Nature》 |2010年第7296期|p.368-372|共5页
  • 作者

    Xunwei Wu; Bach-Cuc Nguyen; Piotr Dziunycz; Sungeun Chang; Yang Brooks; Karine Lefort; Guenther F. L. Hofbauer; G. Paolo Dotto;

  • 作者单位

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA;

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA;

    Department of Dermatology, University Hospital Zurich, Zurich CH-8091;

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA Department of Dermatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea;

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA;

    Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland;

    Department of Dermatology, University Hospital Zurich, Zurich CH-8091;

    Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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