2026-04-17T13:56:21Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1778502025-12-05T09:20:27Zcom_2072_1057col_2072_478799col_2072_478917

00925njm 22002777a 4500 dc Blanco, David author Vicent, Silvestre author Fraga, Mario F. author Fernandez-Garcia, Ignacio author Freire, Javier author Lujambio, Amaia author Esteller, Manel author Ortiz de Solórzano, Carlos author Pio, Ruben author Lecanda, Fernando author Montuenga, Luis M. author 2021-06-01T11:55:47Z 2021-06-01T11:55:47Z 2007-10-01 2021-06-01T11:55:47Z 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. Epigènesi Càncer de pulmó ADN Epigenesis Lung cancer DNA 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