1] Department of Cell and Neurobiology, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Oncogene. 2013 Sep 19;32(38):4565-71. doi: 10.1038/onc.2012.451. Epub 2012 Oct 15.
The tumor suppressor p53 has an important role in inducing cell-intrinsic responses to DNA damage, including cellular senescence or apoptosis, which act to thwart tumor development. It has been shown, however, that senescent or dying cells are capable of eliciting inflammatory responses, which can have pro-tumorigenic effects. Whether DNA damage-induced p53 activity can contribute to senescence- or apoptosis-associated pro-tumorigenic inflammation is unknown. Recently, we generated a p53 knock-out rat via homologous recombination in rat embryonic stem cells. Here we show that in a rat model of inflammation-associated hepatocarcinogenesis, heterozygous deficiency of p53 resulted in attenuated inflammatory responses and ameliorated hepatic cirrhosis and tumorigenesis. Chronic administration of hepatocarcinogenic compound, diethylnitrosamine, led to persistent DNA damage and sustained induction of p53 protein in the wild-type livers, and much less induction in p53 heterozygous livers. Sustained p53 activation subsequent to DNA damage was accompanied by apoptotic rather than senescent hepatic injury, which gave rise to the hepatic inflammatory responses. In contrast, the non-hepatocarcinogenic agent, carbon tetrachloride, failed to induce p53, and caused a similar degree of chronic hepatic inflammation and cirrhosis in wild type and p53 heterozygous rats. These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, especially in livers exposed to agents that inflict lasting mutagenic DNA damage.
抑癌基因 p53 在诱导细胞固有对 DNA 损伤的反应中起着重要作用，包括细胞衰老或凋亡，这可阻止肿瘤的发展。然而，已经表明衰老或死亡的细胞能够引发炎症反应，这可能具有促肿瘤发生的作用。DNA 损伤诱导的 p53 活性是否可以促进与衰老或凋亡相关的促肿瘤炎症尚不清楚。最近，我们通过同源重组在大鼠胚胎干细胞中生成了 p53 敲除大鼠。在这里，我们表明在炎症相关的肝癌发生大鼠模型中，p53 的杂合子缺失导致炎症反应减弱，肝纤维化和肿瘤发生得到改善。肝癌发生化合物二乙基亚硝胺的慢性给药导致野生型肝脏中持续的 DNA 损伤和 p53 蛋白的持续诱导，而在 p53 杂合子肝脏中诱导的 p53 蛋白则较少。DNA 损伤后持续的 p53 激活伴随着凋亡而不是衰老的肝损伤，从而引发了肝炎症反应。相比之下，非致癌剂四氯化碳未能诱导 p53，并导致野生型和 p53 杂合子大鼠中发生相似程度的慢性肝炎症和纤维化。这些结果表明，尽管 p53 通常被认为是一种肿瘤抑制基因，但它的持续激活可以促进促肿瘤炎症，特别是在暴露于造成持久致突变 DNA 损伤的试剂的肝脏中。
