From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms

Inflammation represents the body's natural response to tissue damage; however, chronic inflammation may activate cell proliferation and induce deregulation of cell death in affected tissues. Chronic inflammation is an important factor in the development of hepatocellular carcinoma (HCC), although the precise underlying mechanism remains unknown. Epigenetic events, which are considered key mechanisms in the regulation of gene activity states, are also commonly deregulated in HCC. Here, we review the evidence that chronic inflammation might deregulate epigenetic processes, thus promoting oncogenic transformation, and we propose a working hypothesis that epigenetic deregulation is an underlying mechanism by which inflammation might promote HCC development. In this scenario, different components of the inflammatory response might directly and indirectly induce changes in epigenetic machineries ('epigenetic switch'), including those involved in setting and propagating normal patterns of DNA methylation, histone modifications and non-coding RNAs in hepatocytes. We discuss the possibility that self-reinforcing cross-talk between inflammation and epigenetic mechanisms might amplify inflammatory signals and maintain a chronic state of inflammation culminating in cancer development. The potential role of inflammation-epigenome interactions in the emergence and maintenance of cancer stem cells is also discussed.