Published online Mar 28, 2014. doi: 10.3748/wjg.v20.i12.3078
Revised: November 20, 2013
Accepted: January 6, 2014
Published online: March 28, 2014
The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutations, genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci, nodules, and finally, overt HCC. As well as many other neoplasias, liver cancer is considered an “inflammatory cancer”, arising from a context of inflammation, and characterized by inflammation-related mechanisms that favor tumor cell survival, proliferation, and invasion. Molecular mechanisms that link inflammation and neoplasia have been widely investigated, and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species. The latter, in turn, probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation, and ultimately leading to cancer. The relationship amongst chronic liver injury, free radical production, and development of HCC is explored in the present review, particularly in the light of the complex network that involves oxidative DNA damage, cytokine synthesis, telomere dysfunction, and microRNA regulation.
Core tip: In this review, the relationship amongst chronic liver injury, free radical production, and development of hepatocellular carcinoma is explored. The review confirms the existence, in the intricate pathway involved in the progression of virus-related liver injury to cirrhosis and cancer, of a link between oxidative genomic and mitochondrial damage and telomere dysfunction. This link develops in the context of inflammatory response and induces a derangement of mechanisms controlling liver proliferation. In this scenario, mitochondria are emerging as a possible target for new treatments aimed at counteracting oxidative damage and disease progression to cancer, given their relevant role in inflammation and carcinogenesis.