The Age-Specific Features and Clinical Significance of NRF2 and MAPK10 Expression in HCC Patients

Manar Atyah; Chenhao Zhou; Qiang Zhou; Wanyong Chen; Jialei Weng; Pengcheng Wang; Yi Shi; Qiongzhu Dong; Ning Ren

doi:10.2147/IJGM.S351263

The Age-Specific Features and Clinical Significance of NRF2 and MAPK10 Expression in HCC Patients

Int J Gen Med. 2022 Jan 20:15:737-748. doi: 10.2147/IJGM.S351263. eCollection 2022.

Authors

Manar Atyah^#¹, Chenhao Zhou^#¹, Qiang Zhou¹, Wanyong Chen¹, Jialei Weng¹, Pengcheng Wang¹, Yi Shi², Qiongzhu Dong^{3

4}, Ning Ren^{1

3}

Affiliations

¹ Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, People's Republic of China.
² Biomedical Research Centre, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
³ Institute of Fudan Minhang Academic Health System, and Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, 201199, People's Republic of China.
⁴ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.

^# Contributed equally.

Abstract

Background: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) functions decline with age; however, cancer cells can hijack its pathways to ensure survival and aggressiveness. Yet, the role of NRF2 in hepatocellular carcinoma (HCC) is rarely investigated in an age-specific manner. This study investigates the expression of NRF2 and its activator (MAPK10) in different age groups of HCC patients, in addition to the age-specific features of NRF2 and MAPK10 interaction and their clinical significance.

Methods: Tumor and near-tumor tissue samples of 181 HCC patients were used to complete a protein expression analysis of NRF2 and MAPK10. Patients' survival and clinical data were collected for clinical analysis. Global databases (TCGA, ICGC) were used to collect MAPK10 genetic mutation and mRNA expression data in patients with HCC, colorectal, stomach, and pancreatic cancers.

Results: Our findings revealed an increase in NRF2 protein expression but only in younger HCC patients, along with a decline in MAPK10 ability to activate NRF2 in older patients. We also found an increased MAPK10 genetic mutation rate and decreased mRNA expression in older patients. Low MAPK10 and NRF2 expression levels were associated with shorter survival and poorer prognosis due to positive correlation with microvascular invasion, tumor thrombus, elevated AFP levels, and larger tumor size.

Conclusion: NRF2 expression and oxidative stress mechanism in HCC patients are influenced by age. This magnifies the need to consider patients' age in treatment strategies and guidelines and re-evaluates the application of studies' age-standardized findings in older patients who are usually excluded from relevant research.

Keywords: MAPK10; NRF2; aging; hepatocellular carcinoma; oxidative stress.

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (82073208, 82103521), the Special Foundation for Science and Technology Basic Research Program (2019FY101103) the Shanghai Sailing Program (21YF1407500), the Shanghai Shen Kang Hospital Development Center new frontier technology joint project (SHDC12021109), and the China Postdoctoral Science Foundation (2021M690674).