Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)
Introduction
Liver cancer is the fifth most common cancer and the second leading cause of cancer related deaths worldwide (Ferlay et al., 2012). The major risk factors include hepatitis B (HBV) and hepatitis C (HCV), obesity/metabolic syndrome, and alcoholism which all may progress to hepatocellular carcinoma (HCC). In the last two decades the rising rates of obesity/metabolic syndrome have led to the increased development of the non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Experimental and epidemic studies have shown relationships between NASH and HCC development. Alcoholic liver disease (ALD) and ASH are the major causes of HCC in US (Morgan et al., 2004; Ramadori et al., 2017; Testino et al., 2014). NASH has similar histological features with alcoholic hepatitis, such as overt lipid deposition and fat storage in the liver parenchymal cells. Both ASH and NASH may progress to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC), about 7–10% of NASH may progress to cirrhosis (Scaglioni et al., 2011) and 0.5% to HCC (Lindenmeyer and McCullough, 2018), while 10–20% of ASH progress to cirrhosis (Schwartz and Reinus, 2012; Dam-Larsen et al., 2004) and 7–10% to HCC (Schwartz and Reinus, 2012), annually. Our previous published work showed that there are different molecules protein changes in ASH compared with NASH (Nguyen et al., 2018; Lu et al., 2018)
The mechanisms by which NASH and ASH progress to HCC are not completely understood and there are many theories including chromosomal loss of tumor suppressor genes, oxidative stress, decreased liver retinoic acid level, altered DNA methylation, and genetic susceptibility (Morgan et al., 2004; Stickel et al., 2002; Stickel, 2015). In our previous studies, we showed that in addition to the TLR/NFKB/CXCR4/7 (Liu et al., 2014; French et al., 2012a, French et al., 2012b; Nan et al., 2005; French et al., 2010) and PI3K/AKT/mTORC1 signaling pathways (Afifiyan et al., 2017a, Afifiyan et al., 2017b), Tec kinase signaling pathway connects these two systems together in Mallory-Denk Bodies (MDB) formation both in ASH and NASH (Afifiyan et al., 2017a, Afifiyan et al., 2017b). During these studies we found that HLA-F-adjacent transcript 10 (FAT10), a ubiquitin-like modifier protein which functions as a proteasomal degradation signal (Schmidtke et al., 2009; Rani et al., 2012; Hipp et al., 2005), plays an important role in MDB formation and tumorigenesis (Oliva et al., 2010; Oliva et al., 2008; French et al., 2012a, French et al., 2012b) and we proved that MDB forming cells express preneoplastic phenotypic features (Nan et al., 2006). To confirm the roles of FAT10 and other related molecules in HCC tumorigenesis in NASH and ASH, we studied the changes of FAT10, FOXO1, and ADRA2A in liver biopsy specimens from NASH and ASH patients and control groups.
Section snippets
Methods
Formalin-fixed paraffin-embedded biopsies of ASH liver (n = 39 in FAT10, 50 in FOXO1, 40 in ADRA2A), NASH liver (n = 30), and normal liver (n = 20) were collected from Harbor-UCLA Medical Center and from the Long Beach Veterans Affairs' clinical trial in treatment of alcoholic hepatitis. The study was conducted following the principals of the Declaration of Helsinki and was designated as exempt by our institutional ethics review board and the data was analyzed anonymously. The primary
Results
The protein expression level of several candidate molecules in specimens from patients with ASH, NASH, and normal controls were compared. Representative data are shown in Fig. 1, Fig. 2, Fig. 3.
In ASH patients, levels of all tested candidate proteins including FAT10, FOXO1, and ADRA2A (Fig. 1, Fig. 2, Fig. 3) were markedly increased compared with the control group. In NASH patients, FAT10 and ADRA2A were upregulated when compared to control group, while FOXO1 level was not changed (Fig. 2).
The
Discussion and conclusions
The increasing rates of obesity and the metabolic syndrome become a major health problem worldwide which is emphasized by the relationship from NASH to cirrhosis and even HCC. Wong et al. showed that NASH is the most rapid growing risk for liver transplantation in patients with HCC (Wong et al., 2014, Wong et al., 2015). Chronic (longer than 10 years) alcohol consumption (>80 g/day) increases the risk for HCC approximately 5 fold (French, 2013). ALD is the most common cause of HCC which
Acknowledgements
This study was funded by NIH/AAA grant # UO-21898-05.
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