From actinic keratosis to invasive squamous cell carcinoma: Impact of AHR and p27KIP1 on malignant transformation

从光化性角化病到浸润性鳞状细胞癌：AHR 和 p27KIP1 对恶性转化的影响

• 批准号: 511942584
• 负责人: Privatdozent Dr. Thomas Haarmann-Stemmann
• 金额: --
• 依托单位: Leibniz-Institut für umweltmedizinische Forschung (IUF)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511942584?language=en
• 关键词: actinic; keratosis; invasive; squamous; cell

The incidence of cutaneous squamous cell carcinomas (SCC) has been increasing steadily for years. The most important risk factor for the development of this malignancy is the chronic exposure to ultraviolet (UV) radiation. The majority of SCC arises from actinic keratosis (AK), a precancerous precursor which predominantly occurs on sun-exposed skin areas. Interestingly, only a small percentage of AK develops into invasive SCC. The underlying molecular mechanisms driving this process of malignant transformation are not well understood. In the context of photocarcinogenesis, we have shown that the aryl hydrocarbon receptor (AHR), a transcription factor, which is activated in epidermal cells by photoproducts of the amino acid tryptophan, regulates DNA damage-dependent responses in UVB-exposed keratinocytes. Specifically, AHR inhibits both DNA repair and apoptosis by modulating the intracellular localization and the protein level of the tumor suppressor p27KIP1 (p27). Studies on extracutaneous cancers revealed that a mislocalization of p27 in the cytoplasm induced migration, invasion and other processes, which contribute to the malignant transformation. Further preliminary data indicate that proinflammatory cytokines inhibit the metabolism of AHR-activating tryptophan photoproducts, thereby amplifying the activation of the AHR-p27 axis. In the current project, we will test the hypothesis that an inflammatory micromilieu fosters the accumulation of AHR agonists and the subsequent activation of the, in this context, oncogenic AHR-p27 axis. As a result, AK cells lose their contact inhibition, enhance their motility and grow invasive, finally leading to their transformation into malignant SCC cells. In order to test our working hypothesis, we will investigate whether 1.) an inhibition of CYP1A enzyme activity by inflammatory mediators, such as TNFα, is sufficient to induce or amplify AHR-dependent signaling pathways in AK cells, 2.) an activation of AHR in the presence of inflammatory mediators results in a cytosolic mislocalization and/or proteolysis of the p27 protein, 3.) an activation of the AHR-p27 axis induces the malignant transformation of AK cells in vitro and in vivo, and 4.) comparative immune-/histological staining and RNAseq analyses (cells, xenograft mouse model, clinical samples) enable us to identify AK-specific prognostic signatures. The overall aim of this research project is to identify and validate the AHR-p27 axis as a molecular target for chemopreventive measures to reduce the transformation rate of premalignant AK.

皮肤鳞状细胞癌(SCC)的发病率多年来一直在稳步上升。这种恶性肿瘤发生的最重要的危险因素是长期暴露在紫外线辐射下。大多数鳞状细胞癌发生于光化性角化病(AK)，这是一种癌前病变，主要发生在暴露在阳光下的皮肤区域。有趣的是，只有一小部分AK发展为侵袭性鳞癌。推动这一恶变过程的潜在分子机制尚不清楚。在光致癌的背景下，我们已经证明了芳烃受体(AHR)，一种转录因子，在表皮细胞中被氨基酸色氨酸的光产物激活，调节UVB暴露的角质形成细胞中DNA损伤依赖的反应。具体地说，AHR通过调节肿瘤抑制基因p27KIP1(P27)的细胞内定位和蛋白水平，抑制DNA修复和细胞凋亡。对皮外癌的研究表明，p27在细胞质中的错误定位导致了迁移、侵袭和其他过程，这些过程促成了恶性转化。进一步的初步数据表明，促炎细胞因子抑制激活AHR的色氨酸光产物的代谢，从而放大AHR-p27轴的激活。在目前的项目中，我们将测试炎性微环境促进AHR激动剂积累和随后激活致癌AHR-p27轴的假设。其结果是，AK细胞失去了接触抑制，运动能力增强，生长侵袭，最终导致其转化为恶性鳞癌细胞。为了测试我们的工作假设，我们将调查1。)炎症介质，如肿瘤坏死因子α对细胞色素P1A酶活性的抑制足以诱导或放大AK细胞中依赖于AHR的信号通路。在炎症介质存在的情况下，AHR的激活导致p27蛋白的胞浆错误定位和/或蛋白降解，3)。AHR-p27轴的激活在体内外诱导AK细胞恶性转化。比较免疫/组织学染色和RNAseq分析(细胞、异种移植小鼠模型、临床标本)使我们能够识别AK特异性的预后标志。本研究的总体目标是确定并验证AHR-p27轴作为降低癌前AK转化率的化学预防措施的分子靶点。