Role of Asxl2 in non‑alcoholic steatohepatitis‑related hepatocellular carcinoma developed from diabetes

Abstract

The present study investigated the mechanism(s) of non-alcoholic steatohepatitis-related hepatocellular carcinoma (NASH-HCC) developed from diabetes. Streptozotocin and a high-fat diet (STZ-HFD) were used to induce NASH-HCC in ApoE −/− mice. Mouse liver functions were evaluated by H&E staining, liver/body weight and serum biochemical analysis. The expression levels of inflammation-associated factors were determined by RT-qPCR. Gene expression profiles related to molecular functions and pathways of NASH-HCC were examined by principal component analysis, heatmap, gene ontology and KEGG pathway enrichment analysis. Differentially expressed genes (DEGs) in tumor tissues were confirmed by RT-qPCR. The expression of Asxl2 in human NASH-HCC, other HCC tissues and HCC cells was measured by western blot (WB analysis) and RT-qPCR. For SNU-182 cells transfected with siAsxl2 or Hep3B cells with Asxl2 overexpression, cell proliferation, cell cycle, migration and invasion were respectively determined by CCK-8 assays, flow cytometry, wounding healing and Transwell assays. The expression levels of cell metastasis- and cycle-related proteins were determined by WB analysis and RT-qPCR. NASH-HCC model mice exhibited tumor protrusion with severe steatosis. The blood glucose concentration, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and low-density lipoprotein (LDL), total bile acid (TBA) and the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, glypican 3 (GPC3) and transforming growth factor (TGF)-β were all increased in NASH-HCC model mice. DEGs were mainly related to chromosome organization, the cell cycle and the mitogen-activated kinase (MAPK) pathway. Asxl2 was significantly downregulated in HCC tissues and cells, and this regulated cell growth, migration and invasion. The gene expression pattern, related molecular functions and signaling pathways of NASH-HCC differed from those of normal liver tissues. Additionally, the downregulation of Asxl2 may play a potential role in development of NASH-HCC in patients with diabetes.

HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway

“…Many studies have also reported that knocking out or knocking down CD14 or TLR4 can make experimental animals gain resistance to NAFLD [ 32 , 34 , 49 , 50 ]. In addition, activation of the MAPK/NFκB signaling pathway through different pathways can induce inflammatory responses and exacerbate NAFLD, and much evidence has been obtained [ [51] , [52] , [53] , [54] ]. The use of different drugs to inhibit the activation of MAPK/NFκB signaling pathways through different pathways can improve NAFLD and slow down its development [ 51 , 55 , 56 ].…”

Additional Sex Combs-like Family Associated with Epigenetic Regulation

“…ASXL2 is also associated with solid tumors. Elevated ASXL2 expression is linked to poor survival and is correlated with the prognosis of breast, colorectal, and pancreatic cancers [21,55,56], whereas its downregulation is associated with hepatocellular carcinoma [57]. In mice, ASXL2 loss leads to myeloid leukemia, suggesting a dual role in tumorigenesis.…”

Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential

“…In non-alcoholic fatty liver disease mice, a high-fat diet can induce HCC. Following initiation of the obesogenic diet, the mice developed obesity, insulin resistance, hypertriglyceridemia, and elevated LDL-C, and eventually developed HCC ( 157 , 158 ). Besides, LDLR and cholesteryl ester levels are higher in the murine HCC tissues ( 159 ).…”