芳香烃受体调控NF-κB通路介导的炎症反应在日光性角化病中的作用和机制研究

Actinic keratosis (AK) is a common precancerous disease associated with UVB. The mechanism of UVB inducing AK is not fully understood. In recent years, many studies show that UVB induces skin produce a kind of light products FICZ, FICZ can activate the aryl hydrocarbon receptor (AHR) associated with tumor growth. Our group identified the expression of AHR in AK was significantly increased and activated, AHR regulated the NF-κB passway(p65)and downstream IL-6,Cox-2 expression;AHR may regulate the NF-κB pathway depend on P38MAPK. We speculated that the UVB/AHR/NF-κB signaling pathway is an important signal pathway of AK development. This research intends to adopt AK patients skin，NHEK cell，AK cell and mice model，and with the technical of RCM and RNA interference and overexpression，to study the role of AHR in the initiation and development of AK. Add the signaling pathway inhibitor and luciferase report gene,to study the method of the UVB/AHR/NF-κB signaling pathways transmission and downstream transcription regulation and verify the role of this pathway and downstream inflammatory factors in the ininitiation and development of AK.This study will offer the theoretical basis for the prevention and control of the AK and other UV-induced skin disease.

日光性角化病（AK）是临床常见的与UVB有关的皮肤癌前病变，发病机制不清。近来研究发现UVB可诱导皮肤产生光产物FICZ，进而激活与肿瘤发生有关的芳香烃受体（AHR）通路。课题组前期发现AHR在AK皮损中表达显著升高并激活；AHR可调控NF-κB信号通路（p65）及下游炎症因子IL-6，Cox-2表达；AHR通过P38MAPK调控NF-κB通路。我们推测UVB/AHR/NF-κB信号通路激活是AK发生发展重要机制。本研究拟采用AK患者皮损、NHEK细胞、AK细胞及小鼠模型，结合RNA干扰和过表达、皮肤CT等技术，研究AHR在AK发生发展中的作用；加入信号通路抑制剂和荧光素酶报告基因，验证UVB/AHR/NF-κB信号通路的传递和相关炎症因子的转录调控，明确AHR调控NF-κB通路及相关炎症因子在AK发生发展中的作用和机制。为揭示AK及其它光线性皮肤病发生机制和防治提供新的靶位和理论依据。

日光性角化病（AK）是临床常见的与UVB有关的皮肤癌前病变，AK会进展皮肤鳞状细胞癌。由AK发展而来的皮肤肿瘤恶性程度高，易转移。UVB是导致AK的主要病因，但UVB导致AK的发病机制不清。本研究通过对患者皮损组织、人表皮形成细胞培养和动物模型的建立，使用RNA干扰、Realtime-PCR、免疫印迹法等实验方法研究了芳香烃受体（AHR）在皮肤日光性角化病（AK）发病中的作用，并对其可能的机制NF-κB通路进行了研究。结果：①AHR在人正常皮肤、AK皮损和鳞状细胞癌皮损中表达有明显差异。②AHR可以调控UVB诱导正常人皮肤角质形成细胞（NHEK细胞）IL-6和Cox-2表达。③证实AHR可以调控NF-κB通路 ④AHR调控UVB诱导NHEK细胞IL-6和Cox-2表达与NF-κB信号通路有关。⑤AHR可能通过P38 MAPK通路来调控NF-κB信号通路。结论：研究在国际上首次探讨了AhR在人皮肤上的表达特性以及AhR信号途径在AK发病中的作用，并且发现AHR通过NF-κB通路调控下游相关基因是AK发病的重要机制，研究为皮肤肿瘤的发生机制和防治提供了新的证据和靶位。