GASTROINTESTINAL , HEPATOBILIARY , AND PANCREATIC PATHOLOGY Cytoglobin De fi ciency Promotes Liver Cancer Development from Hepatosteatosis through Activation of the Oxidative Stress Pathway

opyright a 2015 American Society for Inve ublished by Elsevier Inc. All rights reserved ttp://dx.doi.org/10.1016/j.ajpath.2014.12.017 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 acidedefined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCs ) or Cygb / (HSCs ) 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 null and Cygb siRNA-transfectedHSCs 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. (Am J Pathol 2015, 185: 1045e1060; http://dx.doi.org/10.1016/j.ajpath.2014.12.017)