Academic journal article Alcohol Research: Current Reviews

Epigenetic Events in Liver Cancer Resulting from Alcoholic Liver Disease

Academic journal article Alcohol Research: Current Reviews

Epigenetic Events in Liver Cancer Resulting from Alcoholic Liver Disease

Article excerpt

The molecular pathogenesis of liver cancer (i.e., hepatocellular carcinoma [HCC]) is a multistep process that involves both genetic changes, such as chromosomal abnormalities and mutations of the DNA sequence (i.e., somatic mutations), and epigenetic mechanisms, such as chemical modifications of the DNA and the histone proteins around which the DNA is wrapped to form the chromosomes, microRNA posttranscriptional regulators, and changes in various signaling pathways (Wong et al. 2010). This review will focus on the epigenetic phenomena that contribute to the pathogenesis of HCC resulting from alcoholic liver disease (ALD).

Does ALD Lead to HCC Formation?

According to some studies, ALD is the most common cause of HCC, accounting for approximately one-third of all HCC cases (Morgan et al. 2004). Chronic alcohol use of greater than 80 g/day (or approximately three standard drinks or more per day) for more than 10 years increases the risk for HCC approximately fivefold. In patients with decompensated alcoholic cirrhosis, in whom the liver damage is so extensive that the functional portions of the organ can no longer compensate for the damaged ones, the risk of developing HCC approaches 1 percent per year, and this risk does not decrease with abstinence (Morgan et al. 2004). However, HCC also can occur in patients with noncirrhotic ALD. Finally, HCC is more likely to develop 1 to 10 years after the cessation of drinking by ALD patients. Therefore, HCC in these patients is not directly caused by alcohol consumption (Donato et al. 2002).

Alcohol abuse also has synergistic effects with other risk factors for the development of HCC, such as infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), diabetes, and obesity (Hassan et al. 2002; Loomb et al. 2010; Morgan et al. 2004). For example, studies in Italy (Tagger et al. 1999) and the United States (Hassan et al. 2002) found that in patients with HCV infection, alcohol consumption over 80 g/day increased the odds ratio of developing HCC by 7.3 and 4.5, respectively. Likewise, a study conducted in Africa (Mohamed et al. 1992) determined a synergism between HBV and alcohol consumption over 80 g/day in the development of HCC (odds ratio of 4.4).

What Do ALD, HCV, and HBV Have in Common?

The livers of patients who develop HCCs commonly are cirrhotic. Moreover, they often contain molecules (i.e., markers) indicating that the cells undergo changes in their structure and function to a less specialized (i.e., less differentiated) state. These progenitor/ stem cell markers mainly are found in the cirrhotic portion of the liver and in the regions where the HCC develops. These changes and markers have been observed in the livers of patients developing HCC associated with ALD, HBV, and HCV (Oliva et al. 2010). The reversion of normal liver cells (i.e., hepatocytes) into progenitor and stem cells is caused by epigenetic mechanisms. For example, during the development of the progenitor and stem cells, changes occur in the expression of several genes that result from the addition of too many or fewer-than-normal methyl groups to the DNA (i.e., DNA hyper- and hypomethylation, respectively). This alteration of methylation patterns results in an epigenetic reprogramming of the cells (Alison et al. 2009; Collas 2009; Iacobuzio-Donohue 2009; Ohm and Baylin 2009; Richly et al. 2010; Sasaki 2006; Sawan et al. 2008). In addition, modification (i.e., methylation and the addition of acetyl groups [acetylation]) of the histone proteins play roles in the epigenetic modification of progenitor and stem cells that underlies the transformation into cancer cells (i.e., a carcinoma) (Iacobuzio-Donohue 2009). Alcohol excess can induce all of these epigenetic changes that contribute to the transformation of hepatocytes into progenitor or stem cells.

How Does Alcohol Generate Epigenetic Changes?

DNA Methylation

One step in the metabolism of beverage alcohol (i. …

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