Mutant p53 Attenuates the Anti-Tumorigenic Activity of Fibroblasts-Secreted Interferon Beta

Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables individual monitoring of the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNβ) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNβ on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNβ treatment.

p53抑癌蛋白（tumor suppressor protein）突变在肿瘤中极为常见，且通常会赋予细胞致瘤能力。本研究旨在探究突变型p53在肿瘤细胞与周围肿瘤基质（stroma）的细胞串扰（cross-talk）中可能发挥的作用，而该串扰是影响肿瘤预后的关键因素。本研究构建了一种新型共培养模型，可分别监测肿瘤细胞与基质成纤维细胞（fibroblasts）在共培养过程中的应答反应。研究发现，成纤维细胞与肿瘤细胞接触后会激活干扰素β（IFNβ）信号通路，进而抑制自身的迁移能力。肿瘤内的突变型p53可通过细胞因子信号转导抑制因子1（SOCS1）介导的信号转导与转录激活因子1（STAT1）磷酸化抑制，缓解这一应答反应。而干扰素β（IFNβ）则可通过限制突变型p53的RNA稳定因子WIG1，降低其RNA水平。上述研究结果凸显了肿瘤微环境（tumor microenvironment）中突变型p53的致癌特性，并提示突变型p53阳性的肿瘤患者或可从干扰素β治疗中获益。