Hepatocellular Carcinoma - Methyltransferase expression

Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers and there are 630,000 new cases diagnosed every year worldwide (De Minicis et al. 2013). HCC develops frequently from chronic hepatitis or cirrhosis of the liver (Thorgeirsson and Grisham 2002). These conditions result in hepatocyte destruction and promotion of immune cell invasion of the liver tissue, which in turn results in changes of the matrix and micro-environment of the liver (Bosch et al. 1999).

About 80% of HCC develops from hepatitis B virus (HBV), hepatitis C virus (HCV) and aflatoxin B1 (AFB) (Bosch et al. 1999). The development of HCC can take nearly 30 years after infection is first diagnosed (Guo et al. 2004). This infection results in altered hepatocyctes and develops altered hepatocyte signalling which results in hepatocellular carcinoma.

Interestingly, the deregulation of bile acid levels has also been linked to be a promoter of hepatocellular carcinoma in mice when the farnesoid X receptor (FXR, NR1H4) is knocked down (Yang et al. 2007). Bile acids are synthesised in the liver and secreted into the intestine to facilitate absorption of lipids (Hofmann 1999). Interestingly, bile acids act as signalling molecules that can promote liver regeneneration and tumourigenesis (Huang et al. 2006) Importantly, bile acid??induced liver toxicity is regulated by FXR a nuclear receptor or small heterodimer partner (SHP) and they absorbs bile acids into the cell, thus facilitating a negative feedback resulting in the inhibition of bile acid production (Goodwin et al. 2000).

In the preneoplastic phase of HCC, alterations in gene expression by epigenetic changes are one of the first phases of the disease. The altered proliferation of hepatocytes is a result of the increased expression of transforming growth factor- β (TGF-β) and insulin-like growth factor-2 (IGF-2) which is important in hepatocyte proliferation (Kawakita et al. 1992). Interestingly, the up-regulation of TGF-β and IGF-2 is a result of cytokines produced from infiltrating inflammatory cells, viral transactivation and the regenerative response from the liver (Thorgeirsson and Grisham 2002).

The expression of DNA methyltransferases (DMNTs) are upregulated in HCC and these enzymes catalyse the methylation or demethylation of CpG island groups that may play a role in hepatocarcinogenesis (Saito et al. 2001). Furthermore, epigenetic factors that lead to HCC development includes chromatin acetylation resulting in cis/trans-activation of genes from the functioning viral molecules (Thorgeirsson and Grisham 2002).

A number of signalling molecules play a role in the progression of HCC. PTEN is a tumour suppressor and plays a role in regulating the AKT pathway by dephosphorylating the serine-threonine kinase AKT. The down regulation of PTEN results in an increase in hepatocyte hyper-proliferation, anti-apoptosis and oncogenesis. PTEN knock-out mice develop HCC (Horie et al. 2004, Watanabe et al. 2007).

The Wnt signalling pathway, which plays a role in cell growth, is deregulated in HCC. The dephosphorylation of β-catenin and the up-regulation of frizzled-7 have been identified in HCC (Merle et al. 2005, Terris et al. 1999). The tumour suppressor p53 has been identified to play a critical role in HCC development. Studies have shown mutations and inactivation of p53 in HCC (De Minicis et al. 2013).

The MAPK pathway has been identified in regulating HCC; the expression of p21 is increased and the activity of Ras is increased in tumours or cancer cell lines (Calvisi et al. 2006, Jagirdar et al. 1989). IQGAP1 has been shown to be upregulated in HCC while IQGAP2 is down regulated (Xia et al. 2014).The MST2/Hippo pathway has been identified as a key regulator of apoptosis, cell cycle regulation and cell proliferation, and plays a role in HCC development (Yu and Guan 2013).

Interestingly, the expression of YAP1 results in HCC formation, and mice with MST1/2 knock-outs development HCC (Dong et al. 2007, Song et al. 2010).

There is a wealth of information in the basic research of HCC development but the treatment of HCC is limited to the stage of the disease. The first and most effective treatment of HCC is the surgical resection of the tumour (De Minicis et al. 2013). Liver transplantation is viewed is a better option for the treatment of HCC (de Lope et al. 2012). The most widely used drug in the management of HCC is Sorafenib, which inhibits a wide variety of kinases that regulate angiogenesis and cell proliferation. Sorafenib improves patient survival and is now administered as standard in advanced HCC (Llovet et al. 2008).

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