Pathology of Diseases

METHYLATION
1. HCC
  1. METHLYATION MISREGULATION Fish Study(1): Discusses how the METHLYATION MISREGULATION can be a key step in carcinogenesis. Hypomethylation of genes in distal cells from the HCC can trigger neoplasia in these cells themselves. S-adenosylhomocysteine is elevated in these cells, a potent inhibitor of DNA methyltransferase, preventing methylationa and causing misregulartion. EPIGENETIC PROGENITOR MODEL. This is particularly relavent in the liver as disease progresses from liver fibrosis to HCC
  2. OVERALL HYPOMETHYLATION 2)Large number of genes hypomethylated in HCC. 61,058/62,292: supports claim that hypomethlyation is a key aspect (Link to fish study). Global hypomethylation leads to genomic instability whilst specific promoter hypermethylation silences TSGs are key epigenetic mechanisms. Imp to consider changes to methlyation as a hallmark of cancer?
  3. Key TSGs in HCC have been identifed to be significant: SMPD3/NEFH are silenced by methylation. Also hypermethlyation of 37 key TSGs such as p16/retinoblastoma 2. Explain importance of silencing of TSGs in oncogenesis (4)
  4. VIRAL INFLUENCE ON HCC: Oncogenic viral proteins in HBC/HCV induce tumours via an epigenetic mechanism, via hypermethylation of key TSGs. (5) Intragenic CpG islands are demethylated by HBx (in HBV) directly suppressing Dnmt3L and Dnmt 3A promoters, leading to a hypomethylation of intagenic CpG islands, whose methlyation is important for regulation of active expression. Furthermore, HBx induces the expression of DNMT1, leadng to the hypermethylation of key TSGs p16(INK) and IGFBP-3. (6)
2. LIVER FIBROSIS
  1. PPAR gamma (regulator of gene expression of inflammatory mediators in liver injury). Hypermethylation of the promotor region of this gene was significantly associated with liver fibrosis in chronic Hep B patients (8)
  2. Hypomethylation has found to be an important step in early onset liver fibrosis, changing to the hypermethylation of key genes in its progression to HCC. Initial hypomethlation promotes instability in the genome, whilst silencing of key TSGs allows for oncogenesis. (7)
  3. Activation of Hepatic stellate cells is a key feature of Liver fibrosis, from quinescent to myofibroblastic cells. the hypermethylation of PTCH1 and its silencing is key for the progession of fibrosis. (9)
3. NAFLD
  1. Nonalcoholic fatty liver disease is a clinical condition that has many stages ranging from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). SS is usually benign, but NASH can progress to cirrhosis and hepatocellular carcinoma.(14)
  2. Methylation of MT-ND6 in the liver is higher in NASH than SS patients, consequently transcriptional activity and protein expression were significantly decreased in NASH patients. This suggests that expression of this mitochondrial gene, which is regulated by epigenetic modification, plays a major part in the pathogenesis of disease progression in NAFLD. mitochondrial cristae and changes in mitochondrial shape and size.(14)(15)
  3. Maintaining levels of MT-ND5 is important to produce complex I, the largest enzyme complex of the OXPHOS system. A dysfunction in this system results in mitochondrial dysfunction leading to morphological changes such as loss of mitochondrial cristae and changes in mitochondrial shape and size.(14)
HISTONE MODIFICATION
1. ACETYLATION
  1. HCC
    1. SIRT1 is a key modulator of cell proliferation, apoptosis and cell metabolism. It is a deacetylase enzyme, targeting p53 and c-Myc. Deacetylation of the nonhistone protein YAP 2 upregualtes YAP2/TEAD4 causing cell growth in HCC. (9)
    2. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter.
    3. Many cases of HCC are usually associated with chronic viral infections of hepatitis B and hepatitis C, and studies have shown that alterations in histone modifying enzymes help lead to viral induced hepato-carcinogenesis. For example the oncogenic X-protein of hepatitis B virus has been shown to interact directly with the complex CBP/p300 histone acetyl-transferase leading to de-regulation of gene expression and consequently predisposition to tumorigenesis. In addition X protein was also found to interact with histone deacetylase 1, to induce the up-regulation of β-catenin thus conferring resistance to anti-cancer treatments. (16)
  2. NAFLD
    1. Reduction of SIRT1 binding on histone H3 at the CD36 promoter leads to upregulation of CD36 in Men1 knockout hepatocytes. Our results suggest menin-SIRT1 interaction regulates fat accumulation in hepatocytes . Menin recruits SIRT1 to control hepatic CD36 expression and triglyceride accumulation through histone deacetylation.(10)
miRNA
1. Also a viral influence on miRNAs. HBV and HCV can lead to an overexpression of methyltransferases, important for remodelling chromatin to a transcriptionally active state. This overexpression silences miRNAs in the genome, so no post transcriptional regulation of gene expression. (12)
2. miRNAs only recently discovered to be highly involved in gene expression regulation
3. NAFLD
  1. However, have been shown to have a negative role in NAFLD: miR-24 has been proven to promote hepatic lipid accumulation, contributing to NAFLD. (13)
  2. MiRNA-122 accounts for nearly 70% of all miRNAs in the liver, it affects in vivo cholesterol biosynthesis and has been shown to promote adipocyte differentiataion. It is severely underexpressed in NAFLD patients compared to control groups. Recent animal studies show that the genetic deletion of miR-122 in mice causes hepatic steatosis, inflammation, and HCC. When miR-122 was repressed plasma cholesterol level, hepatic fatty-acid and cholesterol synthesis rate, and the level of hydroxy-methyl-glutaryl coenzyme A reductase (HMGCR) that produces cholesterol, were also significantly decreased. This shows that miR-122 is an important regulator of lipid metabolism in the liver and acts as a tumor-suppressor in the liver.(15)
4. HCC
  1. Role of miRNAs just being uncovered: through the expression of miR-520d: caused loss of malignant cell properties in vivo, cancer cells to normal cells and upregulates p53 (11), a very interesting prospect for the reversal of cancer
  2. Many studies have shown the connection of deregulated expression of microRNA (miRNA) in different stages of HCC development. MiRNA are endogenous suppressors of gene expression, as they bind RNA-induced silencing complex to the 3’UTR of target mRNAs. This either causes mRNA degradation if the miRNA binds completely, or translational repression if the binding is incomplete. Overexpression of miRNA in human cancers can up-regulate gene transcription during cell cycle arrest, suggesting they have probable oncogenic functions.(16)(17)
  3. At the same time both HBV and HCV are proven to promote hepatocarcinogenesis through deregulation of host-derived miRNAs.(16)

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	Created by Jason Young over 10 years ago