Expression of proteins upregulated in hepatocellular carcinoma in patients with alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH): An immunohistochemical analysis of candidate proteins

Abstract

Both non-alcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) can lead to cirrhosis and hepatocellular carcinoma. However, the rate of progression to cirrhosis and tumorigenesis in AH is greater than that in NASH. We asked whether there are differences between the two conditions in the expression levels of proteins involved in the pathogenesis of hepatocellular carcinoma. The proteins tested were presented at the 2017 American Association for the Study of Liver Diseases (AASLD) Liver Meeting as overexpressed in hepatocellular carcinoma: KLF4, SCL19A1, FANCG, HRH-1, DNMT1, DNMT3B, TNFR2, DUSP4, EGFR, Integrin α6, HDACII, PDE3A, BCL-XL, and MTCO2. The expression of these proteins was measured in liver biopsy sections from NASH and AH patients using immunohistochemical staining with fluorescent antibodies and then quantifying the fluorescence intensity morphometrically. In AH patients, levels of all tested proteins except HRH-1 were elevated compared to normal patients. In NASH patients, KLF4, SCL19A1, FANCG, HDACII, BCL-XL levels were increased compared to normal controls while HRH-1, DNMT1 and PDE3A levels were decreased. The relative expression of all proteins studied except BCL-XL was significantly higher in AH compared to NASH. In conclusion, proteins involved in hepatocellular cancer development are more highly expressed in AH compared to NASH and normal liver, which corresponds with the higher rate of tumorigenesis in AH patients compared to NASH patients.

Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)

“…It is well accepted that the rates of those progressing to cirrhosis or HCC annually are lower in the NASH if compared with those in ASH. Our published data support that different molecules or pathways may be involved in ASH compared with NASH during the tumorigenesis [Nguyen et al, 2018][Lu et al, 2018] Our work also showed that the TLR/NFKB/CXCR4/7 [Liu et al, 2014][French et al, 2012] [Nan et al, 2010], PI3K/AKT/mTORC1 signaling pathways [Afifiyan et al, 2017], and Tec kinase signaling pathway connected each other during MDB formation both in ASH and NASH [Afifiyan et al, 2017]. …”

“…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 et al, 2018], while 10–20% of ASH progress to cirrhosis [Schwartz et al, 2012][Dam-Larsen et al, 2004] and 7–10% to HCC [Schwartz et al, 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 Roles of Epigenetic Regulators and Inflammasome in Hepatocellular Carcinoma Tumorigenesis in Patients with Alcoholic Steatohepatitis (ASH) vs Non-Alcoholic Steatohepatitis (NASH)

“…Our published data support that different molecules or pathways may be involved in NASH compared with ASH during the tumorigenesis [12,13]. We showed that the TLR/NFKB/CXCR4/7, PI3K/AKT/mTORC1, and Tec kinase signaling pathways connected with each other during MDB formation both in ASH and NASH [11][12][13][14][15][16][17][18][19][20]24].…”

“…The difference in the expression of G9a protein between ASH and NASH groups was statistic significant (Fig. 1) [11,12]. Histidine phosphorylation has broader roles in protein and cellular function including cell cycle regulation, phagocytosis, and tumorigenesis.…”

“…Although there are many theories including genetic alterations of tumor suppressor genes, oxidative stress, and decreased liver retinoic acid level, the detailed mechanisms underlying tumorigenesis of HCC in NASH and ASH patients are not completely understood [2,9,10]. Our previous work found different gene and protein changes in ASH compared with NASH, such as the TLR/NFKB/CXCR4/7, PI3K/AKT/mTORC1 signaling pathways; Ras/RASSF1A/P53 and RUNX3/p53/GSTP1 cross links together in molecular change both in ASH and NASH [11][12][13][14][15][16][17][18][19][20]. The present study attempted to identify the role of epigenetic modulator proteins and inflammasome components in ASH and NASH patients.…”