鳞状细胞型胰腺癌转基因小鼠模型的建立及其分子机制的研究

Based on differential expression of transcription factors and downstream targets, pancreatic cancers have been categorised into four subtypes; squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). Among these four types of pancreatic cancer, the squamous subtype has the worst prognosis and some of the key features of this subtype are high ∆NP63 expression and its target genes. We have found that overexpression of ΔNp63α appears at stage IIA of Pancreatic Intraepithelial Neoplasia (PanIN) lesions and its overexpression is correlated with the invasion, progression and prognosis of pancreatic cancer. This evidence indicates that ΔNp63α plays an important role in the development and progression of pancreatic cancer with unknown mechanisms. There is currently no reported mouse model that mimics human squamous pancreatic cancer with overexpression of ΔNp63α, which could be used to investigate the roles of ΔNp63α expression in the development and progression of pancreatic cancer. We have recently successfully established the ΔNp63α functionally regulated transgenic mouse model with specific expression of ΔNp63α in the pancreas. In this project, we will create squamous pancreatic cancer mouse models by breeding our established ΔNp63α model with K-ras G12D pancreas transgenic mouse model and p53R172H pancreas transgenic mouse model. We will investigate the molecular mechanisms of this type of pancreatic cancer in these models to explore targets for early diagnosis and better treatment, and provide a new platform to evaluate therapeutics for squamous pancreatic cancer.

根据基因转录因子及其靶向基因的差异性表达，胰腺癌可分为鳞状细胞，胰腺多能干细胞，ADEX 和免疫原性四种亚型，其中鳞状细胞亚型的预后最差，它的一个重要特征是∆Np63及其靶基因表达上调。最近我们发现ΔNp63α过度表达出现在胰腺上皮内瘤变（PanIN）2A期，其高表达与胰腺癌浸润、发展和预后差密切相关。这些证据表明ΔNp63α在胰腺癌的发生和进展中发挥重要的作用，但其作用机制尚不清楚。目前缺乏小鼠模型模拟人的过度表达ΔNp63α的鳞状细胞型胰腺癌。最近我们成功建立了在胰腺中特异性表达而且功能上可调控的ΔNp63α转基因小鼠模型，我们将在本课题中结合此小鼠模型与 K-ras G12D，p53R172H胰腺癌转基因小鼠模型，建立过度表达ΔNp63α的鳞状细胞型胰腺癌的小鼠模型，研究此类胰腺癌的分子发病机制，为其早期诊断和更好地治疗提供依据，并且为评价这种类型胰腺癌的治疗方法提供新的平台。

根据基因转录因子及其靶向基因的差异性表达，胰腺癌可分为鳞状细胞，胰腺多能干细胞，ADEX 和免疫原性四种亚型，其中鳞状细胞亚型的预后最差，它的一个重要特征是ΔNp63α及其靶基因表达上调。最近我们发现ΔNp63α过度表达出现在胰腺上皮内瘤变（PanIN）2A期，其高表达与胰腺癌浸润、发展和预后差密切相关。这些证据表明ΔNp63α在胰腺癌的发生发展中发挥重要的作用，但其作用机制尚不清楚。目前缺乏小鼠模型模拟人的过度表达ΔNp63α的鳞状细胞型胰腺癌。在此项目中我们成功建立了在胰腺中特异性表达而且功能上可调控的ΔNp63α转基因小鼠模型，同时结合此小鼠模型与 K-ras G12D，p53R172H胰腺癌转基因小鼠模型，建立过度表达ΔNp63α的鳞状细胞型胰腺癌的小鼠模型，同时在体外我们探究了ΔNp63α影响胰腺癌发生发展的相关机制，对于模拟胰腺癌的发生发展以及后续治疗胰腺癌以及治疗胰腺癌的新药测评具有重大意义。