Oxidative damage in the progression of chronic liver disease to hepatocellular carcinoma: an intricate pathway.
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.
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Romilda
R
Cardin
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Marika
M
Piciocchi
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Marina
M
Bortolami
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Andromachi
A
Kotsafti
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Luisa
L
Barzon
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Enrico
E
Lavezzo
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Alessandro
A
Sinigaglia
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Kryssia Isabel
KI
Rodriguez-Castro
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Massimo
M
Rugge
Romilda Cardin, Marika Piciocchi, Marina Bortolami, Andromachi Kotsafti, Kryssia Isabel Rodriguez-Castro, Fabio Farinati, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Fabio
F
Farinati
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004260:DNA Repair; D018450:Disease Progression; D058625:End Stage Liver Disease / Q000473:pathology*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012737:Sex Factors; D016615:Telomere / Q000648:ultrastructure
D000975:Antioxidants; D016207:Cytokines; D035683:MicroRNAs; D017382:Reactive Oxygen Species
Antioxidant mechanisms; Cytokines; Hepatocellular carcinoma; MicroRNA and circulating free DNA; Reactive oxygen species; Telomere dysfunction; Viral hepatitis; mitochondria