Interleukin-33 in skin carcinogenesis

项目概要： 非黑色素瘤皮肤癌（NMSC），包括基底细胞癌（BCC）和鳞状细胞癌（SCC）。 癌（SCC）是最常诊断的癌症，在美国每年有超过一百万的新病例。 我们在主要的NMSC亚型中，SCC具有更大的转移和死亡风险。虽然死亡率 与其他一些癌症类型相比，SCC的发病率并不高， 干预措施。因此，SCC可导致患者的显著发病率和经济负担。 SCC发展的最重要的风险因素之一是来自太阳的紫外线（UV）暴露。 紫外线损伤DNA，导致皮肤表面的上皮角质细胞突变， 从而导致肿瘤的形成。此外，紫外线暴露诱导强烈的皮肤炎症反应， 我们的小组和其他人已经证明，炎症反应和炎症是皮肤癌发生的驱动因素。 最近，相对较新描述的细胞因子IL-33的功能已开始在皮肤中描述。 除了包括在本申请中的初步数据之外，几项研究已经表明IL-33刺激细胞凋亡。 皮肤发炎。此外，最近发表的数据和我们的初步结果表明，IL-33 在炎症高峰期暴露于UV后，角质形成细胞中的表达上调。我们 初步数据还显示IL-33由鼠和人皮肤肿瘤中的肿瘤细胞表达。因此 到目前为止，关于IL-33在任何癌症类型（包括皮肤）中的作用的信息很少;然而， 在紫外线的上调及其在皮肤炎症中的作用方面，IL-33可能是一个关键因素， 皮肤癌发生的介质。 拟议研究的中心假设是，IL-33通过改变UV-1水平促进皮肤癌发生。 诱发炎症。将执行以下特定目标来检验此假设：目标1 -检查 IL-33在UV诱导的炎症中的作用;目的2 -确定IL-33在UV诱导的炎症中的重要性。 皮肤致癌作用总的来说，这些实验将产生关于IL-33的有价值的新信息。 SCC的发展和增长，并将是确定是否合乎逻辑的发展的第一步 旨在阻断IL-33作用的治疗策略。 .

PROJECT SUMMARY: Non-melanoma skin cancers (NMSC), which include basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), are the most commonly diagnosed cancers with over a million new cases annually in the US. Of the main NMSC subtypes, SCC has a greater risk for metastasis and mortality. While the mortality rate is not as high for SCC compared to some other cancer types, there are very few effective non-surgical interventions. As a result, SCC can lead to significant morbidity and financial burden for patients. One of the most important risk factors for SCC development is ultraviolet light (UV) exposure from the sun. UV damages the DNA, leading to mutations in epithelial keratinocytes on the surface of the skin and consequently, to the formation of tumors. Additionally, UV exposure induces a robust cutaneous inflammatory response, and inflammation has been shown by our group as well as others to drive skin carcinogenesis. Recently, the function of the relatively newly described cytokine, IL-33, has started to be described in the skin. Several studies in addition to preliminary data included in this application have shown that IL-33 stimulates inflammation in the skin. Furthermore, recently published data and our preliminary results show that IL-33 expression is upregulated in keratinocytes after UV exposure during times of peak inflammation. Our preliminary data also show that IL-33 is expressed by tumor cells in both murine and human skin tumors. Thus far, there is very little information about the role of IL-33 in any cancer type, including the skin; however, based on its upregulation by UV and its demonstrated role in cutaneous inflammation, IL-33 is likely to be a key mediator of skin carcinogenesis. The central hypothesis of the proposed studies is that IL-33 promotes skin carcinogenesis by altering UV- induced inflammation. The following Specific Aims will be carried out to test this hypothesis: Aim 1 - Examine the function of IL-33 in UV-induced inflammation; Aim 2 - Determine the importance of IL-33 in UV-induced skin carcinogenesis. Overall, these experiments will generate valuable new information about IL-33 in the development and growth of SCC and will be the first steps in determining whether it is logical to develop treatment strategies aimed at blocking the effects of IL-33. .