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

Keii To; Kosuke Okada; Takahisa Watahiki; Hideo Suzuki; Kiichiro Tsuchiya; Katsutoshi Tokushige; Masakazu Yamamoto; Shun-Ichi Ariizumi; Junichi Shoda

doi:10.1002/cam4.6538

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

Cancer Med. 2023 Oct;12(19):19423-19437. doi: 10.1002/cam4.6538. Epub 2023 Sep 21.

Authors

Keii To^{1

2}, Kosuke Okada^{1

3}, Takahisa Watahiki¹, Hideo Suzuki¹, Kiichiro Tsuchiya¹, Katsutoshi Tokushige⁴, Masakazu Yamamoto⁵, Shun-Ichi Ariizumi⁵, Junichi Shoda³

Affiliations

¹ Department of Gastroenterology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
² Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
³ Division of Medical Sciences, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
⁴ Institute of Gastroenterology and Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan.
⁵ Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: KEAP1; NASH; NRF2; chronic liver disease; hepatocellular carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular* / pathology
Fibrosis
Humans
Inflammation / metabolism
Kelch-Like ECH-Associated Protein 1 / metabolism
Liver / pathology
Liver Cirrhosis / pathology
Liver Neoplasms* / pathology
NF-E2-Related Factor 2 / metabolism
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2

Associated data

UMIN-CTR/UMIN000037080