皮肤鳞状细胞癌的组织学特征是鳞状细胞的过度增殖和分化水平的降低。目前，皮肤鳞状细胞癌具体的发病原因和机制尚不清楚，早期诊治缺乏针对性。Raf1是Ras/MAPK信号通路中的重要成员，该通路与皮肤表皮异常分化及皮肤肿瘤形成密切相关。申请人前期研究发现RIPK4 (Receptor-interacting protein kinase 4) 能够促进皮肤表皮细胞分化，抑制皮肤鳞状细胞癌形成，并且 Raf1是皮肤鳞状细胞癌中RIPK4的结合配体。本项目拟利用前期研究成功构建的RIPK4条件性敲除小鼠，从细胞分化、增殖、凋亡三方面研究RIPK4抑制皮肤鳞状细胞癌形成的细胞学机制；从RIPK4结合Raf1的条件、方式、位点及结合形成的RIPK4/Raf1复合物抑癌作用研究RIPK4拮抗Raf1抑制皮肤鳞状细胞癌的分子机制。上述研究将有助于深入认识皮肤鳞状细胞癌发生的新型机制，发掘新的治疗靶点。

Cutaneous squamous cell carcinoma is characterized by excessive proliferation and low differentiation of squamous cells. However, the pathogenesis and underlying molecular mechanism of cutaneous squamous cell carcinoma remains poorly understood. Raf1 protein is the essential component of Ras/MAPK signaling cascade, whose deregulation is strongly associated with skin tissue homeostasis and carcinogenesis. Our previous study indicated that RIPK4 (Receptor-interacting protein kinase 4), a novel serine/threonine kinase, could suppress skin carcinogenesis by enhancing epidermal differentiation and binding Raf1. To decipher the underlying cellular mechanism, we will analyze epidermal differentiation, cell proliferation and cell apoptosis in RIPK4 conditional knockout mice. We will further characterize the interaction between RIPK4 and Raf1 and decipher the molecular mechanisms whereby RIPK4 governs epidermal homeostasis and skin carcinogenesis. The results of this project will shed light on the elaborating mechanism and therapeutic targets of skin squamous cell carcinoma.