Transcription profiling of mouse stratified epithelial spontaneous SCC induced by the somatic inactivation of Rb1 and Trp53 tumor suppressors

The squamous cell carcinomas represent the aggressive type of non melanoma skin cancer, the most frequent malignancy among human population. We have studied here the possible relationship between these two pathways in skin using epidermal-specific mutant mice. Loss of p53, but not pRb, produces spontaneous tumor development, indicating that, contrary to pRb, p53 is the predominant tumor suppressor acting in mouse epidermis. The simultaneous inactivation of pRb and p53 does not aggravate the epidermal phenotype observed in Rb-deficient mice in terms of proliferation and/or differentiation. However, in doubly deficient mice spontaneous skin tumor development is severely accelerated. The tumors are aggressive, undifferentiated and display a hair follicle origin. Detailed analysis indicates that the acceleration is mediated by premature activation of the EGFR/Akt pathway, resulting in increased angiogenesis. The molecular characteristics of this model provide valuable tools to understand epidermal tumor formation, and may ultimately contribute to the development of therapies for the treatment of aggressive squamous cancer. Experiment Overall Design: Pools from RNA whole skin extracts from 3 animals of same genotype were done and analyzed, per duplicate, in mouse microarrays. Comparison was performed between the 4 different genotypes.鳞状细胞癌（squamous cell carcinomas）属于侵袭性非黑色素瘤皮肤癌（non-melanoma skin cancer），是人类群体中最常见的恶性肿瘤。本研究利用表皮特异性突变小鼠（epidermal-specific mutant mice），探究了皮肤内两条通路间的潜在关联。敲除p53（而非pRb）可引发自发性肿瘤生成，这表明与pRb不同，p53是小鼠表皮中起主要作用的抑癌基因。同时失活pRb与p53，并未在增殖和/或分化层面加重Rb缺陷小鼠（Rb-deficient mice）中观察到的表皮表型。但在双基因缺陷小鼠（doubly deficient mice）中，自发性皮肤肿瘤的发生会被显著加速。此类肿瘤具有侵袭性、未分化特性，且起源于毛囊。详细分析显示，该加速效应由EGFR/Akt通路（EGFR/Akt pathway）的过早激活所介导，进而导致血管生成（angiogenesis）增强。本模型的分子特征为理解表皮肿瘤形成机制提供了宝贵工具，或最终可为侵袭性鳞状细胞癌的治疗手段开发提供助力。实验总体设计：将相同基因型的3只小鼠的全皮肤RNA提取物进行混合，每份混合样本设置两次生物学重复，随后在小鼠基因芯片（mouse microarrays）上开展分析，并对4种不同基因型的样本进行比对。