芹菜素调控miRNA-RECK信号通路抑制皮肤鳞状上皮细胞癌转移的机制研究

芹菜素能够抑制UV暴露和化学致癌物所诱发的皮肤癌，然而其中的具体机制尚未阐明。我们前期发现：1）miR-7-1-3p和miR-125a-3p受UVB的诱导，而芹菜素会显著减少其表达；2）UVB会降低人角质形成细胞中的RECK水平，而芹菜素会恢复RECK的表达；3）UVB会增加活MMP-2/MMP-9的生成量，并且芹菜素会抑制UVB的作用；4）芹菜素可以抑制在UVB照射后的表面真皮中的微血管密度(MVD)。综上，我们提出以下构想：芹菜素通过抑制UVB诱导的miRNA（miR-7-1-3p和miR-125a-3p）恢复RECK表达，导致MMP活性降低，从而减少侵袭/转移和血管生成，抑制UVB诱发皮肤癌。本项目拟在前期研究基础上，通过基因芯片、动物模型、双荧光素酶报告基因、基因干扰、阻断剂等实验，深入研究芹菜素调控miRNA-RECK通路抑制皮肤癌。

Ultraviolet B(UVB) radiation is the major carcinogen for skin cancer,and apigenin inhibits non-melanoma skin cancer induced by both UV exposure and chemical carcinogens.However,the molecular mechanisms of apigenin action are only partially understood.Our novel preliminary results demonstrate that miR-7-1-3p and miR-125a-3p are induced by UVB and apigenin markedly decreases their expression.Besides,UVB decreases RECK levels in human keratinocytes and apigenin restores the expression of RECK.In addition,we found that UVB increases active MMP-2/MMP-9 production and apigenin suppresses UVB’s effect. Finally,apigen inhibits microvascular density(MVD) in the superficial dermis that occurs in response to UVB irradiation.Based on these preliminary findings,the present project is designed to explore deeper insights into the molecular mechanism(s) by which apigenin inhibits the progression of skin cancer via regulation of miRNA-RECK signaling,using genetic and pharmacological approaches including GeneChip microarray,luciferase reporter assay,RNA interference,small molecule inhibitors,etc.In this proposal,we hypothesize that apigenin restores RECK expression through inhibition of UVB-induced miRNAs(miR-7-1-3p and miR-125a-3p),leading to decreased MMP activity thereby reducing invasion/metastasis and angiogenesis to prevent UVB-induced skin cancer.Linking miRNAs to apigenin’s beneficial effects,further identifying RECK as a potential target and demonstrating its important role in apigenin’s chemopreventive function will provide a new strategy for better prevention of skin cancer.