Laboratorio Nazionale CIB (LNCIB), AREA Science Park, 34149 Trieste, Italy.
Laboratorio Nazionale CIB (LNCIB), AREA Science Park, 34149 Trieste, Italy; Dip. Scienze della Vita, Università degli Studi di Trieste, 34127 Trieste, Italy.
Mol Cell. 2014 Dec 4;56(5):617-29. doi: 10.1016/j.molcel.2014.10.013. Epub 2014 Nov 13.
Inflammation is a significant factor in cancer development, and a molecular understanding of the parameters dictating the impact of inflammation on cancers could significantly improve treatment. The tumor suppressor p53 is frequently mutated in cancer, and p53 missense mutants (mutp53) can acquire oncogenic properties. We report that cancer cells with mutp53 respond to inflammatory cytokines increasing their invasive behavior. Notably, this action is coupled to expression of chemokines that can expose the tumor to host immunity, potentially affecting response to therapy. Mechanistically, mutp53 fuels NF-κB activation while it dampens activation of ASK1/JNK by TNFα, and this action depends on mutp53 binding and inhibiting the tumor suppressor DAB2IP in the cytoplasm. Interfering with such interaction reduced aggressiveness of cancer cells in xenografts. This interaction is an unexplored mechanism by which mutant p53 can influence tumor evolution, with implications for our understanding of the complex role of inflammation in cancer.
炎症是癌症发展的一个重要因素，对决定炎症对癌症影响的参数的分子理解，可以显著改善治疗效果。肿瘤抑制因子 p53 在癌症中经常发生突变，而 p53 错义突变体（mutp53）可以获得致癌特性。我们报告称，具有 mutp53 的癌细胞对炎性细胞因子的反应会增加其侵袭行为。值得注意的是，这种作用与趋化因子的表达相关，趋化因子可以使肿瘤暴露于宿主免疫之下，从而可能影响对治疗的反应。从机制上讲，mutp53 促进 NF-κB 的激活，同时抑制 TNFα 对 ASK1/JNK 的激活，而这种作用依赖于 mutp53 在细胞质中与肿瘤抑制因子 DAB2IP 的结合和抑制。干扰这种相互作用可降低异种移植中癌细胞的侵袭性。这种相互作用是突变型 p53 影响肿瘤进化的一个未被探索的机制，这对我们理解炎症在癌症中的复杂作用具有重要意义。
