Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.
Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.
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DOI：
10.18632/oncotarget.4296
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发表时间：
2015-09-08
期刊：
影响因子：
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通讯作者：
Soler C
中科院分区：
文献类型：
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作者：
Manils J;Gómez D;Salla-Martret M;Fischer H;Fye JM;Marzo E;Marruecos L;Serrano I;Salgado R;Rodrigo JP;Garcia-Pedrero JM;Serafin AM;Cañas X;Benito C;Toll A;Forcales SV;Perrino FW;Eckhart L;Soler C
TREX2是角质形成细胞中特异表达的3‘-DNA核酸外切酶。在这里，我们研究了TREX2在紫外线(UV)诱导的皮肤癌发生中的相关性和机制。TREX2在慢性紫外线照射下表达上调，而在人鳞状细胞癌(SCCs)中表达下调或缺失。此外，我们发现TREX2基因中的SNPs在头颈部鳞状细胞癌患者中比健康人更常见。在小鼠中，TREX2缺乏导致对UVB诱导的皮肤癌的敏感性增加，在此之前，DNA损伤和降解异常，以及炎症减轻。特别是，TREX2的缺失降低了IL12和干扰素γ的上调，这是与DNA修复和抗肿瘤免疫相关的关键细胞因子。在紫外线处理的角质形成细胞中，TREX2促进DNA修复和进入晚期凋亡阶段。值得注意的是，TREX2被招募到低密度核染色质和微核中，在那里它与磷酸化的H2 AX组蛋白相互作用，组蛋白在DNA修复和细胞死亡中都起着关键作用。总之，我们的数据为TREX2活性的分子机制提供了新的见解，并建立了TREX2在UVB诱导的皮肤反应中的细胞自主和非细胞自主功能。
TREX2 is a 3′-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.