Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.
Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.
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DOI：
10.1016/j.molonc.2016.06.002
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发表时间：
2016-10
影响因子：
6.6
通讯作者：
Spandau DF
中科院分区：
文献类型：
--
作者：
Loesch MM;Collier AE;Southern DH;Ward RE;Tholpady SS;Lewis DA;Travers JB;Spandau DF
胰岛素样生长因子-1受体（IGF-1 R）的激活状态调节角质形成细胞对紫外线B（UVB）暴露的细胞反应，在体外和体内。老年皮肤缺乏IGF-1表达，导致异常的IGF-1 R依赖性UVB反应，这有助于衰老相关鳞状细胞癌的发展。此外，我们的实验室和其他人已经报道，老年角质形成细胞修复UVB诱导的DNA损伤的效率低于年轻的成年角质形成细胞。在这里，我们表明，IGF-1 R激活影响UVB照射的角质形成细胞的DNA损伤修复。具体而言，在IGF-1 R活化的情况下，UVB照射后DNA损伤修复的速率显著减慢（使用永生化的人角质形成细胞）或抑制（使用原代人角质形成细胞）。此外，使用离体外植体培养物或体内异种移植物模型抑制人皮肤中的IGF-1 R活性，抑制DNA损伤修复。具有失活IGF-1 R的原代角质形成细胞也表现出较低的核苷酸切除修复mRNA的稳态水平。这些结果表明，在老年角质形成细胞中UVB诱导的DNA修复缺陷部分是由于老年皮肤中IGF-1 R激活沉默，并提供了一种机制，IGF-1途径如何在老年患者鳞状细胞癌的发生中发挥作用。
The activation status of the insulin-like growth factor-1 receptor (IGF-1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF-1 expression resulting in an aberrant IGF-1R-dependent UVB response which contributes to the development of aging-associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB-induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF-1R activation influences DNA damage repair in UVB-irradiated keratinocytes. Specifically, in the absence of IGF-1R activation, the rate of DNA damage repair following UVB-irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF-1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF-1R also exhibited lower steady-state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB-induced DNA repair in geriatric keratinocytes is due in part to silenced IGF-1R activation in geriatric skin and provide a mechanism for how the IGF-1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients.