Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway
Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway
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DOI：
10.1593/neo.07517
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Montuenga, Luis M.
中科院分区：
文献类型：
--
作者：
Blanco, David;Vicent, Silvestre;Montuenga, Luis M.
炎症介导的肺癌发生的分子标志尚未完全阐明，主要是由于缺乏合适的动物模型。我们已经使用了二氧化硅诱导的多步肺癌模型驱动的慢性炎症，以研究分子标志物和遗传变异的演变。我们分析了DNA损伤反应（DDR）、增殖应激和端粒应激的标志物：γ-H2 AX、p16、p53和TERT。肺癌相关的表观遗传学和遗传学改变，包括p16（CDKN 2A）、APC、CDH 13、Rassf 1和Nore 1A的启动子高甲基化状态，以及Tp 53、表皮生长因子受体、K-ras、N-ras和c-H-ras的突变也已被研究。我们的研究结果表明，在癌前病变的DDR途径激活，与诱导型一氧化氮合酶和p53诱导。p16在早期肿瘤发生发展中也被诱导，在细支气管发育不良和肿瘤中失活。值得注意的是，Ras和表皮生长因子受体突变的缺乏以及非常低频率的Tp 53突变表明它们不是该模型中肿瘤发生所需的。相反，在p16（CDKN 2A），CDH 13和APC，但不是在Rassf 1和Nore 1A的表观遗传学改变，清楚地观察到。这些数据表明，存在一个特定的分子签名的炎症驱动的肺癌，共享一些，但不是全部，化学诱导的肺癌的分子标志。
The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: gamma-H2AX, p16, p53, and TERT. Lung cancer -related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.