Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer.
Interleukin 6 downregulates p53 expression and activity by stimulating ribosome biogenesis: a new pathway connecting inflammation to cancer.
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慢性炎症是癌症发病的既定风险因素，并且炎性细胞因子IL-6通过增强增殖和阻碍凋亡在肿瘤发生中起作用。由于刺激增殖的因子也通过增强核糖体生物合成下调p53表达，我们假设IL-6可能在炎症组织中引起类似的变化，从而激活有利于肿瘤转化的机制。在这里，我们表明，IL-6下调的表达和活性的p53在转化和未转化的人类细胞系。这是IL-6依赖性刺激c-MYC mRNA翻译的结果，这导致rRNA转录上调。增强的rRNA转录通过减少用于MDM 2结合的核糖体蛋白的可用性来刺激MDM 2介导的p53蛋白酶体降解。p53下调诱导获得上皮-间充质转化特征的细胞表型变化，例如E-钙粘蛋白表达水平降低，细胞侵袭力增加和对细胞毒性应激的反应降低。我们发现这些变化也发生在溃疡性结肠炎患者的结肠上皮细胞中，溃疡性结肠炎是一个非常有代表性的慢性炎症高风险肿瘤发展的例子。结肠活检标本的组织化学和免疫组化分析显示，与正常粘膜样品相比，慢性结肠炎中核糖体生物合成上调，p53表达减少，E-钙粘蛋白表达减少或缺失。抗炎药物治疗后，这些变化消失。综上所述，目前的结果突出了一种新的机制，可能将慢性炎症与癌症联系起来，基于p53下调，其通过IL-6暴露后rRNA转录的增强而激活。
Chronic inflammation is an established risk factor for the onset of cancer, and the inflammatory cytokine IL-6 has a role in tumorigenesis by enhancing proliferation and hindering apoptosis. As factors stimulating proliferation also downregulate p53 expression by enhancing ribosome biogenesis, we hypothesized that IL-6 may cause similar changes in inflamed tissues, thus activating a mechanism that favors neoplastic transformation. Here, we showed that IL-6 downregulated the expression and activity of p53 in transformed and untransformed human cell lines. This was the consequence of IL-6-dependent stimulation of c-MYC mRNA translation, which was responsible for the upregulation of rRNA transcription. The enhanced rRNA transcription stimulated the MDM2-mediated proteasomal degradation of p53, by reducing the availability of ribosome proteins for MDM2 binding. The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial–mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses. We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development. Histochemical and immunohistochemical analysis of colon biopsy samples showed an upregulation of ribosome biogenesis, a reduced expression of p53, together with a focal reduction or absence of E-cadherin expression in chronic colitis in comparison with normal mucosa samples. These changes disappeared after treatment with anti-inflammatory drugs. Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.
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