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

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths worldwide. Among others, non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the two major risk factors as both of them may develop cirrhosis and hepatocellular carcinoma (HCC) if left untreated. However, patients with NASH progress to HCC at a rate around 0.5% annually, while 3–10% ASH patients may progress to HCC annually. The present study is to demonstrate the molecular differences in oncogenesis pathway between NASH and ASH. By using immunofluorescence study and quantitating the fluorescence intensity morphometrically in liver biopsied specimens from NASH and ASH patients, the protein expression of candidate molecules within hepatocytes cytoplasm are studied, including two HCC-related molecules FAT10 and FOXO1, and one GPCR pathway related molecule ADRA2A. Compared with the control group patients, the expression levels of all the molecules were upregulated in the ASH group of patients(p<0.001 in all molecules), while FAT10 and ADRA2A were upregulated, FOXO1 did not change in the NASH group of patients.The most important finding is that compared with the ASH group of patients, the expression levels of all three molecules were significantly lower than in the NASH group of patients (p<0.001 in all molecules). These results confirmed our previous finding that there are significant differences of molecules change in ASH compared to NASH. Thus, we conclude that there are significantly different molecules and pathways involved during the pathogenesis of HCC development in ASH compared to NASH which could help explain why the tumorigenic rate is different in ASH and NASH.

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].…”

“…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.…”

The Role of FAT10 in Alcoholic Hepatitis Pathogenesis

“…FAT10 protein expression is up-regulated in ASH but not in NASH or normal controls ( Figure 2 A) which indicates the specific effect of FAT10 in ASH. These results indicate that FAT10 increased in the ASH, compared with control group, and even compared with the NASH specimens [ 41 ].…”

“…Using this technology, we can measure the amount of each protein in the control livers, the AH livers, and the non-alcoholic steatohepatitis (NASH) livers simultaneously, for comparison. Figure 2 shows the immunofluorescence results of the FAT10 protein, where the liver cell cytoplasm and nucleus of the hepatocytes are filled with FAT10 [41]. FAT10 is sequestered within MDBs in alcoholic steatohepatitis (ASH), suggesting that the excess expression of FAT10 in ASH is leading to the stabilization of the protein.…”

“…FAT10 also signals a switch in the 26s proteasome's three proteases to replace them with the three immunoproteases (MEK-1, LMP2, and LMP7) [9]. This causes a failure to turnover proteins in a timely manner, leading to their accumulation and stabilization, but are ubiquitinated and apparently overexpressed [9,14,41,46] (Figure 3). This leads the stabilized proteins to form aggresomes, in the form of MDBs, in response to the overexpression of IFNγ and TNFα [46].…”