Cancer Res.:DNA应激和p53影响肿瘤细胞TOLL样受体表达

6月6日，Cancer Research在线报道，肿瘤细胞中DNA应激和p53状态可差异性影响TOLL样受体固有免疫家族的表达。

转录因子p53调节包括TOLL样受体（TLR）在内的固有免疫相关基因的表达。这提示p53也调节人类免疫反应。TLR家族构成识别病原相关的分子模式(PAMPs)的细胞膜糖蛋白，介导固有免疫反应。TLR激动剂已被用于肿瘤治疗的佐剂。

研究证实，阿霉素、5氟尿嘧啶、紫外线以及电离辐射均可以细胞系和损伤特异性的方式引起TLR表达的改变。特别是，治疗诱导的TLR表达改变可造成其下游细胞因子对相应配体刺激的反应性表达上升。刺激TLR表达的DNA应激压力效应主要由p53介导。P53的几个癌相关突变显著改变TLR基因表达。在所有检测过的细胞系中，TLR3的诱导表达是p53依赖性的，而TLR9则较少依赖p53的状态。此外，所检测的10个固有免疫TLR基因家族成员的可诱导性呈现差异性。

这些发现证实，基于TLR的肿瘤治疗所应该考虑到p53状态、染色体应激和每类TLR分子的反应性等背景因素。

doi:10.1016/j.cell.2011.10.017
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The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells

Maria Shatz1, Daniel Menendez2, and Michael A Resnick3,*

The transcription factor p53 regulates genes associated with a wide range of functions, including the Toll-like receptor (TLR) set of innate immunity genes, suggesting that p53 also modulates the human immune response. The TLR family comprises membrane glycoproteins that recognize pathogen-associated molecular patterns (PAMPs) and mediate innate immune responses, and TLR agonists are being used as adjuvants in cancer treatments. Here, we demonstrate that doxorubicin, 5-fluorouracil, and UV and ionizing radiation elicit changes in TLR expression that are cell line- and damage-specific. Specifically, treatment-induced expression changes led to increased downstream cytokine expression in response to ligand stimulation. The effect of DNA stressors on TLR expression was mainly mediated by p53, and several p53 cancer-associated mutants dramatically altered the pattern of TLR gene expression. In all cell lines tested, TLR3 induction was p53-dependent, while induction of TLR9, the most stress-responsive family member, was less dependent on status of p53. In addition, each of the 10 members of the innate immune TLR gene family tested was differentially inducible. Our findings therefore demonstrate that the matrix of p53 status, chromosome stress, and responsiveness of individual TLRs should be considered in TLR-based cancer therapies.