Immunopositivity for Histone MacroH2A1 Isoforms Marks Steatosis-Associated Hepatocellular Carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously.MethodsWe examined macroH2A1.1 and macroH2A1.2 protein expression levels in the liver of two murine models of fat-associated HCC, the high fat diet/diethylnistrosamine (DEN) and the phosphatase and tensin homolog (PTEN) liver specific knock-out (KO) mouse, and in human liver samples of subjects with steatosis or HCC, using immunoblotting and immunohistochemistry.ResultsProtein levels for both macroH2A1 isoforms were massively upregulated in HCC, whereas macroH2A1.2 was specifically upregulated in steatosis. In addition, examination of human liver samples showed a significant difference (p<0.01) in number of positive nuclei in HCC (100% of tumor cells positive for either macroH2A1.1 or macroH2A1.2), when compared to steatosis (<2% of hepatocytes positive for either isoform). The steatotic areas flanking the tumors were highly immunopositive for macroH2A1.1 and macroH2A1.2.ConclusionsThese data obtained in mice and humans suggest that both macroH2A1 isoforms may play a role in HCC pathogenesis and moreover may be considered as novel diagnostic markers for human HCC.

Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice

“…One section from each liver was then stained with haematoxylin and eosin (H&E) and another with Masson's Trichrome to assess steatosis, inflammation and fibrosis (26). The Brunt-Kleiner NAFLD Activity Score was used to quantitatively assess the degree of injury by an expert liver pathologist blinded to the identity of the groups (27).…”

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

“…Nevertheless, the aging process increases the risk of hepatic functional and structural impairment and metabolic risk. In this respect, mouse models of metabolic syndrome with NAFLD reveal features of accelerated aging, impaired regeneration, and an increased incidence of HCC(2, 3). Interventions to clear senescent hepatocytes in a neoplastic-prone tissue microenvironment delay the emergence of HCC in rats (4).…”

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet

“…[8][9][10][11][18][19][20][21][22] MacroH2A1 KO mice have been generated by two independent groups and they both reported mild metabolic effects. 20,21 To understand if macroH2A1 could have systemic effects on fat accumulation and obesity, we challenged macroH2A1 KO mice with a HFD.…”

“…[14][15][16][17] Interestingly, in mice models of non-alcoholic fatty liver disease (NAFLD), a disorder that is present in 90% of obese subjects, hepatic content of macroH2A1 is augmented. 18,19 Two mice models, knockout (KO) for macroH2A1, have been reported under a standard diet feeding. In the first model, generated in the pure C57Bl/6J background, developmental changes in macroH2A1-mediated gene regulation were observed.…”