Critical role for constitutive type I interferon signaling in the prevention of cellular transformation
Critical role for constitutive type I interferon signaling in the prevention of cellular transformation
复制标题
DOI：
10.1111/j.1349-7006.2008.01051.x
复制
发表时间：
2009-03-01
期刊：
影响因子：
5.7
通讯作者：
Takaoka, Akinori
中科院分区：
文献类型：
--
作者：
Chen, Hui-min;Tanaka, Nobuyuki;Takaoka, Akinori
干扰素-α/β是病毒感染时产生的，是建立抗病毒状态的关键可溶性因素，但在没有感染的情况下也会产生低水平的干扰素。在这里，我们证明了这些成分产生的干扰素-α/β的微弱信号显示了在细胞转化中的预防作用。缺乏干扰素-α/β信号的Ifnar1缺陷(Ifnar1(-/-))MEF在长期细胞培养过程中会发生自发转化。与IRF1(-/-)MEF相似，原代Ifnar1(-/-)MEF通过表达活化的c-Ha-Ras癌蛋白而在裸鼠体内致瘤。然而，Ifnar1(-/-)MEF没有表现出任何异常的生长特性。在不能产生组成性干扰素-α/β的Ifnb(-/-)MEF中也有类似的观察到，而在缺乏任何干扰素受体下游分子包括STAT1、IRF9和IRF1的MEF中没有发现这种转化特性。此外，Ifnar1(-/-)小鼠发生化学诱导的皮肤乳头状瘤比野生型小鼠更严重。此外，人胃癌组织中IFNAR1基因的表达水平显著降低。这些结果表明，弱信号通过组成性产生的干扰素-α/β来阻止细胞转化，这可能是通过干扰素-α/β受体下游一条迄今未知的途径(S)介导的。(《癌症科学》2009；100：449-456)。
Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor. (Cancer Sci 2009; 100: 449-456).