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Epigenetic events in liver cancer resulting from alcoholic liver disease.

French SW - Alcohol Res (2013)

Bottom Line: Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation.Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC.Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harbor UCLA Medical Center, Torrance, California, USA.

ABSTRACT
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

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The signaling molecule p27 is upregulated in the nuclei of liver cells (i.e., hepatocytes) in a liver biopsy from two patients with alcoholic hepatitis. The livers were stained with an immunoperoxidase-labeled antibody that recognizes p27. The hepatocyte nuclei positive for p27 appear brown; those that are negative for p27 appear blue. (A and B) Most of the nuclei stained positive. (B) The Mallory-Denk bodies (MDBs) also stained brown (arrows), indicating that p27 also is sequestered in the MDBs. Magnification ×520.
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f2-arcr-35-1-57: The signaling molecule p27 is upregulated in the nuclei of liver cells (i.e., hepatocytes) in a liver biopsy from two patients with alcoholic hepatitis. The livers were stained with an immunoperoxidase-labeled antibody that recognizes p27. The hepatocyte nuclei positive for p27 appear brown; those that are negative for p27 appear blue. (A and B) Most of the nuclei stained positive. (B) The Mallory-Denk bodies (MDBs) also stained brown (arrows), indicating that p27 also is sequestered in the MDBs. Magnification ×520.

Mentions: The role of p21 and p27 in HCC also is supported by studies showing that both proteins are overexpressed in alcoholic hepatitis and in rats chronically fed ethanol (Crary and Albrecht 1998; French et al. 2012; Koteish et al. 2007) For example, immunohisto-chemical studies of liver samples from patients with alcoholic hepatitis found that many of the cells were positive for p27 (see figure 2), and additional analyses indicated that cell-cycle progression was blocked in these cells as indicated by low numbers of nuclei showing expression of (i.e., positive for) a protein called ki-67 (French et al. 2012). Another study demonstrated that both p21 and p27 overexpression inhibit the regeneration of the liver in rats whose liver had been partially removed (Koteish et al. 2007).


Epigenetic events in liver cancer resulting from alcoholic liver disease.

French SW - Alcohol Res (2013)

The signaling molecule p27 is upregulated in the nuclei of liver cells (i.e., hepatocytes) in a liver biopsy from two patients with alcoholic hepatitis. The livers were stained with an immunoperoxidase-labeled antibody that recognizes p27. The hepatocyte nuclei positive for p27 appear brown; those that are negative for p27 appear blue. (A and B) Most of the nuclei stained positive. (B) The Mallory-Denk bodies (MDBs) also stained brown (arrows), indicating that p27 also is sequestered in the MDBs. Magnification ×520.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860418&req=5

f2-arcr-35-1-57: The signaling molecule p27 is upregulated in the nuclei of liver cells (i.e., hepatocytes) in a liver biopsy from two patients with alcoholic hepatitis. The livers were stained with an immunoperoxidase-labeled antibody that recognizes p27. The hepatocyte nuclei positive for p27 appear brown; those that are negative for p27 appear blue. (A and B) Most of the nuclei stained positive. (B) The Mallory-Denk bodies (MDBs) also stained brown (arrows), indicating that p27 also is sequestered in the MDBs. Magnification ×520.
Mentions: The role of p21 and p27 in HCC also is supported by studies showing that both proteins are overexpressed in alcoholic hepatitis and in rats chronically fed ethanol (Crary and Albrecht 1998; French et al. 2012; Koteish et al. 2007) For example, immunohisto-chemical studies of liver samples from patients with alcoholic hepatitis found that many of the cells were positive for p27 (see figure 2), and additional analyses indicated that cell-cycle progression was blocked in these cells as indicated by low numbers of nuclei showing expression of (i.e., positive for) a protein called ki-67 (French et al. 2012). Another study demonstrated that both p21 and p27 overexpression inhibit the regeneration of the liver in rats whose liver had been partially removed (Koteish et al. 2007).

Bottom Line: Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation.Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC.Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harbor UCLA Medical Center, Torrance, California, USA.

ABSTRACT
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

Show MeSH
Related in: MedlinePlus