KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.
KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.
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KIND1 缺失使角质形成细胞对紫外线诱导的炎症反应和 DNA 损伤敏感。
DOI：
10.1016/j.jid.2016.09.023
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Zhang,JenniferY
中科院分区：
文献类型：
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作者：
Zhang,Xiaoling;Luo,Suju;Wu,Joseph;Zhang,Long;Wang,Wen-Hui;Degan,Simone;Erdmann,Detlev;Hall,Russell;Zhang,JenniferY
KIND 1是一种参与β1-整联蛋白功能的细胞骨架蛋白，其功能丧失可导致Kindler综合征，这是一种以皮肤脆性、光敏性和鳞状细胞癌风险增加为特征的遗传性疾病。Kindler综合征皮肤脆性的基础是β1整合素的失调然而，鳞状细胞癌易感性的潜在机制尚不清楚。在这里，我们证明，KIND 1基因沉默减少角质形成细胞增殖和增加细胞凋亡在体外和皮肤移植再生的小鼠，这是相关的减少cyclinB 1。此外，KIND 1缺失使角质形成细胞对细胞因子和UV诱导的NF-κB和c-Jun N-末端激酶活化以及CXCL 10和肿瘤坏死因子-α的上调敏感。此外，KIND 1丢失损害DNA修复，如UVB辐射后24小时γ H2 AX和环丁烷嘧啶二聚体检测增加所示。遗传或药理学c-Jun N-末端激酶抑制和NF-κB抑制显著减少环丁烷嘧啶二聚体阳性细胞。此外，我们表明，KIND 1在转录水平上受到JunB的调控，并且与JunB一样，它在人鳞状细胞癌细胞中下调。总之，这些结果表明KIND 1不仅对角质形成细胞增殖很重要，而且对抑制UV诱导的炎症和DNA损伤也很重要。这些发现支持KIND 1的肿瘤抑制功能，并确定c-Jun N-末端激酶和NF-κB作为预防Kindler综合征患者鳞状细胞癌的潜在治疗靶点。
Loss of function of KIND1, a cytoskeletal protein involved in β1-integrin function, causes Kindler syndrome, a genetic disease characterized by skin fragility, photosensitivity, and increased risk of squamous cell carcinoma. Dysregulation of β1-integrin underlies Kindler syndrome skin fragility. However, the mechanisms underlying squamous cell carcinoma susceptibility are unclear. Here, we demonstrate that gene silencing of KIND1 decreased keratinocyte proliferation and increased apoptosis in vitro and in skin grafts regenerated on mice, which was correlated with reduced cyclinB1. In addition, KIND1 loss sensitized keratinocytes to cytokine and UV-induced NF-κB and c-Jun N-terminal kinase activation and upregulation of CXCL10 and tumor necrosis factor-α. Moreover, KIND1 loss impaired DNA repair, as indicated by the increased detection of γH2AX and cyclobutane pyrimidine dimers 24 hours after UVB radiation. Genetic or pharmacological c-Jun N-terminal kinase inhibition and NF-κB inhibition markedly reduced cyclobutane pyrimidine dimers-positive cells. Further, we show that KIND1 was regulated by JunB at the transcriptional level and, like JunB, it was downregulated in human squamous cell carcinoma cells. Together, these results indicate that KIND1 is important not only for keratinocyte proliferation but also for the suppression of UV-induced inflammation and DNA damage. These latter findings support a tumor suppressor function for KIND1, and identify c-Jun N-terminal kinase and NF-κB as potential therapeutic targets for prevention of squamous cell carcinoma in patients with Kindler syndrome.