抑癌蛋白p53是恶性肿瘤最重要的调节蛋白之一。在原癌基因刺激下，p53主要受p19Arf蛋白及核糖体蛋白（RP）两条蛋白通路的调控。申请人所在实验室于2010年在国际上首次证明RP对p53的调节存在于动物体内，但其调控癌症发生的明确机制目前并无定论。此课题针对p19Arf蛋白及RP蛋白调节p53功能，进而影响HCC发生的机制进行研究。p53水平正常的肝脏星状细胞会使巨噬细胞攻击衰老细胞以达到抑瘤效果，即具有细胞衰老相关分泌表型（SASP）；而p53缺失的星状细胞则会加速恶性肿瘤生长。本课题将首次制备p53正常组、p53调节组和p53条件性敲除组小鼠模型，并通过慢性肝损伤诱发HCC。比较各组间HCC发生、肝星状细胞的SASP表型之差异，分析各种相关蛋白及基因表达差异，进而探索出RP与p19Arf两种蛋白对于HCC发生及肝星状细胞SASP行为的相关性及机制。

p53 acts as one of the most important tumor suppressors. Abnormalities in its gene are commonly observed in hepatocellular carcinoma (HCC). The p19Arf and the ribosomal protein (RP) are both essential and necessary regulators in preventing oncogene induced tumorigenesis. In 2010, Zhang lab firstly provided studies of the physiology function of RP-Mdm2-p53 pathway in vivo, which is highly related with tumorigenesis, but the mechanism of the regulation is still not clear. This study focus on the two p53 regulation proteins, p19Arf and RP, and their relationship with HCC tumorigenesis. WT p53-expressing stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture (named senescence associated secretory phenotype，SASP), whereas proliferating p53-deficient stellate cells stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Here, we will generate several p53 modulated transgenic mice and p53 conditional knockout mice with the presence of chronic liver damage. We will compare p53 WT group mice, p53 modulate group (p19Arf deletion and/or Mdm2C305F mutation) and p53 conditional knockout group mice for HCC tumorigenesis and SASP of hepatic stellate cells. We are going to investigate the potential mechanism behind the regulation of HCC and SASP by p53 regulator protein p19Arf and RP.