Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC) specific deletion of p53, we demonstrate that single loss of p53 is not sufficient to initiate intestinal tumorigenesis, but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. While during the initiation stage p53 controls DNA damage and IEC survival, during tumor progression, loss of p53 is associated with the formation of an inflammatory microenvironment and activation of NF-kB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function that is independent of its well-established role in cell cycle regulation, apoptosis and senescence. 4 AOM induced cancers derived from Tp53DEIC mice were isolated and DNA was extracted. These were compared to genomic DNA isolated from healthy littermate control animals. Agilent Mouse 4x180K arrays were used (Design ID 27411).

p53缺失被认为可促进结直肠肿瘤从腺瘤（adenoma）进展至癌（carcinoma）阶段。本研究采用肠上皮细胞（intestinal epithelial cell, IEC）特异性敲除p53的小鼠模型，证实仅缺失p53不足以启动肠道肿瘤发生，但可显著提升致癌物诱导的肿瘤发生率，并促成侵袭性癌症与淋巴结转移。在肿瘤起始阶段，p53可调控DNA损伤与肠上皮细胞存活；而在肿瘤进展阶段，p53缺失与炎性微环境形成、NF-κB及Stat3激活密切相关。据此，本研究提出一种全新的p53介导的肿瘤抑制功能，该功能独立于其经典的细胞周期调控、凋亡及衰老抑制作用。本研究分离了4例由偶氮甲烷（azoxymethane, AOM）诱导的Tp53DEIC小鼠来源的肿瘤并提取DNA，将其与健康同窝对照动物的基因组DNA进行比对。实验采用安捷伦小鼠4x180K基因芯片（设计编号27411）。