Immunohistochemical expression of NRF2 is correlated with the magnitude of inflammation and fibrosis in chronic liver disease.

Abstract

The nuclear factor E2-related factor 2-Kelch-like Ech-associated protein (NRF2-KEAP1) pathway is a major cellular defense mechanism against oxidative stress. However, the role of NRF2-KEAP1 signaling in the development of chronic liver disease remains unclear. Clinical liver specimens from 50 hepatocellular carcinoma (HCC) developed from non-alcoholic steatohepatitis (NASH), 49 HCCs developed from chronic viral hepatitis C (CHc), and 48 liver metastases of colorectal cancer (CRC) from both tumorous and non-tumorous areas were collected during hepatic resection surgery. They were evaluated by immunohistochemical analyses of hematoxylin-eosin, Masson's trichrome, NRF2, and KEAP1, and compared with clinicopathological information. Hepatic inflammation and fibrosis were more severe in the low-intensity NRF2 group than in the high-intensity NRF2 group both between CRC and NASH (Low vs. High: inflammation; p = 0.003, fibrosis; p = 0.014), and between CRC and CHc (Low vs. High: inflammation; p = 0.031, fibrosis; p = 0.011), which could indicate that NRF2 expression in cytosol of hepatocytes was inversely correlated with liver inflammation and fibrosis in non-tumorous areas. The dense staining of NRF2 in the nuclei of non-tumor hepatocytes positively correlated with liver inflammation (CRC and NASH; R = 0.451, p < 0.001, CRC and CHc; R = 0.502, p < 0.001) and fibrosis (CRC and NASH; R = 0.566, p < 0.001, CRC and CHc; R = 0.548, p < 0.001) in both NASH and CHc, and was inversely correlated with hepatic spare ability features such as platelet count (R = -0.253, p = 0.002) and prothrombin time (R = -0.206, p = 0.012). However, KEAP1 expression was not correlated with NRF2 expression levels and nuclear staining intensity. Nuclear translocation of NRF2 was correlated with the magnitude of liver inflammation and fibrosis in chronic liver disease. These results suggest that NRF2 plays a protective role in the development of chronic liver diseases such as NASH and CHc.