摘要 2447：TLR4 表达是紫外线照射的人角质形成细胞中 EMT 和应激反应基因表达的决定因素,Cancer Research

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摘要 2447：TLR4 表达是紫外线照射的人角质形成细胞中 EMT 和应激反应基因表达的决定因素
Cancer Research ( IF 12.5 ) Pub Date : 2021-07-01 , DOI: 10.1158/1538-7445.am2021-2447
Viktoria Kirschnerova ₁ , Prajakta Vaishampayan ₁ , Maria Khawam ₁ , Clara Curiel-Lewandrowski ₁ , Georg T. Wondrak ₁ , Sally E. Dickinson ₁

Affiliation

摘要 Toll 样受体 4 (TLR4) 因其在多种癌症相关信号通路中的作用而受到关注，包括炎症调节、DNA 修复和上皮间质转化 (EMT)。有证据表明，TLR4 有助于皮肤细胞（包括角质形成细胞）中紫外线 (UV) 辐射诱导的压力信号传导。使用药理学拮抗剂 resatorvid (TAK-242) 阻断 TLR4 活性不仅在体外和体内抑制急性紫外线诱导的信号传导，而且在小鼠模型中阻断紫外线诱导的皮肤癌发生。为了从基因上探索 TLR4 在角质形成细胞对紫外线诱导的应激反应中的作用，我们最近利用 CRISPR/Cas9 技术从培养的人 HaCaT 角质形成细胞的基因组中删除了 TLR4。第一的，使用差异基因表达分析（采用 EMTRT2 Profiler PCR 阵列技术）观察到 TLR4 KO 状态与独立 RT-qPCR 分析证实的 EMT 相关基因表达（MMP9、VIM、FN1、SNAI1、TWIST1）的显着下调相关. TLR4 也是紫外线诱导的炎症酶表达的决定因素，包括 PTGS2。在表型上，TLR4 KO 细胞表现出基质胶跨孔迁移的衰减。TLR4 KO 细胞表现出对紫外线诱导的细胞凋亡的敏感性增加，如通过膜联蛋白 V/碘化丙啶染色细胞的流式细胞术检测，以及通过免疫检测增加的 PARP 裂解。此外，对长期暴露于致瘤性紫外线的小鼠皮肤的 NanoString nCounter 表达分析表明，局部 resatorvid 治疗与 MMP9 下调有关。未来的研究将采用这种新型 TLR4 KO 角质形成细胞系作为一种机制工具，以剖析 TLR4 在皮肤光损伤和致癌背景下的炎症信号传导和 EMT 反应中的作用。由 NIH 授予 ES029579、R03CA230830、P01CA229112 的支持。引文格式：Viktoria Kirschnerova、Prajakta Vaishampayan、Maria Khawam、Clara Curiel-Lewandrowski、Georg T. Wondrak、Sally E. Dickinson。TLR4 表达是紫外线照射的人角质形成细胞中 EMT 和应激反应基因表达的决定因素[摘要]。在：美国癌症研究协会 2021 年年会论文集；2021 年 4 月 10 日至 15 日和 5 月 17 日至 21 日。费城 (PA)：AACR；癌症研究 2021；81（13_Suppl）：摘要 nr 2447。

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Abstract 2447: TLR4 expression as a determinant of EMT and stress response gene expression in UV exposed human keratinocytes

Abstract Toll-like receptor 4 (TLR4) is gaining attention for its role in several cancer-associated signaling pathways, including the regulation of inflammation, DNA repair and epithelial-mesenchymal transition (EMT). There is evidence that TLR4 contributes to ultraviolet (UV) radiation-induced stress signaling in skin cells, including keratinocytes. Blockade of TLR4 activity using the pharmacological antagonist resatorvid (TAK-242) inhibits not only acute UV-induced signaling in vitro and in vivo, but blocks UV-induced skin carcinogenesis in mouse models. In order to genetically explore the role of TLR4 in keratinocyte responses to UV-induced stress, we recently utilized CRISPR/Cas9 techniques to delete TLR4 from the genome of human HaCaT keratinocyte cells in culture. First, using differential gene expression analysis (employing the EMTRT2 Profiler PCR array technology) it was observed that TLR4 KO status is associated with pronounced downregulation of EMT-related gene expression (MMP9, VIM, FN1, SNAI1, TWIST1) confirmed by independent RT-qPCR analysis. TLR4 was also a determinant of UV-induced inflammatory enzyme expression including PTGS2. Phenotypically, TLR4 KO cells displayed an attenuation of Matrigel transwell migration. TLR4 KO cells demonstrated increased sensitivity to UV-induced apoptosis as detected by flow cytometry of annexin V/propidium iodide stained cells, and by immunodetection of increased PARP cleavage. Moreover, NanoString nCounter expression analysis of murine skin chronically exposed to tumorigenic UV indicated that topical resatorvid treatment was associated with MMP9 downregulation. Future studies will employ this novel TLR4 KO keratinocyte cell line as a mechanistic tool to dissect the role of TLR4 in inflammatory signaling and EMT response in the context of skin photodamage and carcinogenesis. Supported by NIH grants ES029579, R03CA230830, P01CA229112. Citation Format: Viktoria Kirschnerova, Prajakta Vaishampayan, Maria Khawam, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson. TLR4 expression as a determinant of EMT and stress response gene expression in UV exposed human keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2447.

更新日期：2021-07-01

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