Chronic inflammation is causally associated to many types of tumor, and has been recently acknowledged as a cancer hallmark. Nevertheless, whether inflammation has an intrinsic mutagenic potential is still not directly proven or understood from a mechanistic point of view. Furthermore, it is as yet unclear whether inflammation could induce epigenetic modifications, and if these changes are relevant to tumor generation. Therefore, the aim of this work was to assess inflammation-derived genomic and epigenomic modifications at multiple stages of tumorigenesis in Mdr2-knockout mice, a model of purely inflammatory hepatocellular carcinoma (HCC). By ChIPseq profiling of H3K27Ac mark we reported the establishment of an inflammatory program specifically in hepatocytes starting from the pre-malignant, chronic inflammatory step. This inflammatory signature is retained up to the more advanced HCC stage, and is accompanied by the activation of members of the AP1 transcription factor family. In parallel, by whole exome sequencing, we observed a high frequency of copy number amplifications and a very low number of point mutations in HCC nodules. Copy number variations occurrence was directly correlated to the grade of malignancy in each lesion. The JNK pathway was shown to be pervasively targeted by gene amplification, and to be involved in the adenoma-to-carcinoma transition. A comparable genetic landscape has been observed in a human liver cancer with similar etiology. In conclusion, this study shows that in a model of inflammation-driven cancer an epigenetic inflammatory signature is early acquired and maintained throughout disease progression. On the contrary, genetic alterations appear only at later stages and mainly target the JNK pathway. Future dataset integration will help clarifying chronological relationship and possible mutual interplay between mutations and epigenetic changes.
|Titolo:||CHARACTERIZATION OF GENETIC AND EPIGENETIC MODIFICATIONS IN A MODEL OF INFLAMMATION-DRIVEN CANCER|
|Tutor esterno:||NATOLI, GIOACCHINO|
|Data di pubblicazione:||25-mar-2014|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Citazione:||CHARACTERIZATION OF GENETIC AND EPIGENETIC MODIFICATIONS IN A MODEL OF INFLAMMATION-DRIVEN CANCER ; supervisor: G. Natoli. - Milano : Università degli studi di Milano. UNIVERSITA' DEGLI STUDI DI MILANO, 2014 Mar 25. ((25. ciclo, Anno Accademico 2013.|
|Digital Object Identifier (DOI):||10.13130/collino-agnese_phd2014-03-25|
|Appare nelle tipologie:||Tesi di dottorato|