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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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Related in: MedlinePlus

Immunohistochemical analysis of a liver biopsy obtained from a patient with alcoholic hepatitis with Mallory-Denk body (MDB) formation. The samples were stained for the presence of CD49f (integrin subunit α6) (green) and ubiquitin (red). Note that the MDBs stain both red for ubiquitin and green for CD49f. The arrows point to the nuclei that stain green except for the nucleolus. The yellow fringe on the MDB indicates colocalization of both proteins at the interface of the MDBs. The round black holes are macrovesicular fat globules in the hepatocytes. A) (magnification ×700) shows a cluster of MDB-forming cells. B) (magnification ×1,050) shows a single cell forming an MDB.
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f5-arcr-35-1-57: Immunohistochemical analysis of a liver biopsy obtained from a patient with alcoholic hepatitis with Mallory-Denk body (MDB) formation. The samples were stained for the presence of CD49f (integrin subunit α6) (green) and ubiquitin (red). Note that the MDBs stain both red for ubiquitin and green for CD49f. The arrows point to the nuclei that stain green except for the nucleolus. The yellow fringe on the MDB indicates colocalization of both proteins at the interface of the MDBs. The round black holes are macrovesicular fat globules in the hepatocytes. A) (magnification ×700) shows a cluster of MDB-forming cells. B) (magnification ×1,050) shows a single cell forming an MDB.

Mentions: Machida and colleagues (2012) also found that TISCs isolated from the livers of alcohol-fed HCV Ns5a transgenic mice and from alcoholic patients carried molecules called CD133 and CD49f (i.e., were CD133+/CD49f+ cells). CD49f enhances the cell’s ability to differentiate into different cell types (i.e., multipotency) and maintains the cells’ stem-cell–like characteristics by directly controlling the regulatory molecules OCT4 and SOX2 (Yu et al. 2012). In addition, CD49f activates a signaling pathway called the phosphatidylinositol 3-kinase (P13K) AKT pathway and suppresses the levels of a protein called p53, which regulates the cell cycle and acts to prevent tumor formation (i.e., is a tumor suppressor gene). Immunohistochemical analyses of liver biopsies from patients with alcoholic hepatitis that contained numerous MDBs found that these cells expressed high levels of CD49f in the cytoplasm and the nuclei (see figure 5). This finding supports the concept that MDB-forming hepatocytes have progenitor and pluripotential properties and eventually may transform into TISC cells. Furthermore, in mice that were fed DCC and subsequently developed MDBs and, ultimately, HCC, CD49f, in combination with other molecules, induced MDB formation. This process could be blocked by inhibiting the phosphorylation of ERK and thus the activation of this protein as well as MDB formation (Wu et al. 2005).


Epigenetic events in liver cancer resulting from alcoholic liver disease.

French SW - Alcohol Res (2013)

Immunohistochemical analysis of a liver biopsy obtained from a patient with alcoholic hepatitis with Mallory-Denk body (MDB) formation. The samples were stained for the presence of CD49f (integrin subunit α6) (green) and ubiquitin (red). Note that the MDBs stain both red for ubiquitin and green for CD49f. The arrows point to the nuclei that stain green except for the nucleolus. The yellow fringe on the MDB indicates colocalization of both proteins at the interface of the MDBs. The round black holes are macrovesicular fat globules in the hepatocytes. A) (magnification ×700) shows a cluster of MDB-forming cells. B) (magnification ×1,050) shows a single cell forming an MDB.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f5-arcr-35-1-57: Immunohistochemical analysis of a liver biopsy obtained from a patient with alcoholic hepatitis with Mallory-Denk body (MDB) formation. The samples were stained for the presence of CD49f (integrin subunit α6) (green) and ubiquitin (red). Note that the MDBs stain both red for ubiquitin and green for CD49f. The arrows point to the nuclei that stain green except for the nucleolus. The yellow fringe on the MDB indicates colocalization of both proteins at the interface of the MDBs. The round black holes are macrovesicular fat globules in the hepatocytes. A) (magnification ×700) shows a cluster of MDB-forming cells. B) (magnification ×1,050) shows a single cell forming an MDB.
Mentions: Machida and colleagues (2012) also found that TISCs isolated from the livers of alcohol-fed HCV Ns5a transgenic mice and from alcoholic patients carried molecules called CD133 and CD49f (i.e., were CD133+/CD49f+ cells). CD49f enhances the cell’s ability to differentiate into different cell types (i.e., multipotency) and maintains the cells’ stem-cell–like characteristics by directly controlling the regulatory molecules OCT4 and SOX2 (Yu et al. 2012). In addition, CD49f activates a signaling pathway called the phosphatidylinositol 3-kinase (P13K) AKT pathway and suppresses the levels of a protein called p53, which regulates the cell cycle and acts to prevent tumor formation (i.e., is a tumor suppressor gene). Immunohistochemical analyses of liver biopsies from patients with alcoholic hepatitis that contained numerous MDBs found that these cells expressed high levels of CD49f in the cytoplasm and the nuclei (see figure 5). This finding supports the concept that MDB-forming hepatocytes have progenitor and pluripotential properties and eventually may transform into TISC cells. Furthermore, in mice that were fed DCC and subsequently developed MDBs and, ultimately, HCC, CD49f, in combination with other molecules, induced MDB formation. This process could be blocked by inhibiting the phosphorylation of ERK and thus the activation of this protein as well as MDB formation (Wu et al. 2005).

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