Cytoglobin Deficiency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway

Abstract

This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid-defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCs(Cygb-wild)) or Cygb(-/-) (HSCs(Cygb-null)) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCs(Cygb-null) and Cygb siRNA-transfected-HSCs(Cygb-wild) exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.