Wang MQ, Li YP, Xu M, Tian Y, Wu Y, Zhang X, Shi JJ, Dang SS, Jia XL. VCAN, expressed highly in hepatitis B virus-induced hepatocellular carcinoma, is a potential biomarker for immune checkpoint inhibitors. World J Gastrointest Oncol 2022; 14(10): 1933-1948 [PMID: 36310697 DOI: 10.4251/wjgo.v14.i10.1933]
Corresponding Author of This Article
Xiao-Li Jia, Doctor, Chief Doctor, Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xincheng District, Xi’an 710004, Shaanxi Province, China. drjxl.123@xjtu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Mu-Qi Wang, Ya-Ping Li, Yan Tian, Xin Zhang, Juan-Juan Shi, Shuang-Suo Dang, Xiao-Li Jia, Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Meng Xu, Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Yuan Wu, Department of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Author contributions: Jia XL and Dang SS designed the study; Zhang X, Wu Y, Li YP, and Jia XL collected all samples in the study; Wang MQ, Wu Y, and Tian Y collected the data; Wang MQ and Xu M performed the statistical analysis; Wang MQ, Li YP, and Jia XL drafted the manuscript; Xu M, Jia XL, and Li YP made critical revisions to the manuscript; Jia XL, Xu M and Shi JJ provided financial support; and all authors read and approved the manuscript.
Supported bythe National Natural Science Foundation of China, No. 31500650 and 81902449; the Key Research & Development Program-Social Development of Shaanxi Province, No. 2020SF-063; and Shaanxi Key Research and Development Plans, No. 2021SF-227.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committees of the Second Affiliated Hospital of Xi’an Jiaotong University (Approval No. 2019-1093).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Li Jia, Doctor, Chief Doctor, Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xincheng District, Xi’an 710004, Shaanxi Province, China. drjxl.123@xjtu.edu.cn
Received: May 21, 2022 Peer-review started: May 21, 2022 First decision: July 13, 2022 Revised: July 23, 2022 Accepted: September 12, 2022 Article in press: September 12, 2022 Published online: October 15, 2022 Processing time: 145 Days and 20 Hours
Abstract
BACKGROUND
As a proteoglycan, VCAN exists in the tumor microenvironment and regulates tumor proliferation, invasion, and metastasis, but its role in hepatocellular carcinoma (HCC) has not yet been elucidated.
AIM
To investigate the expression and potential mechanism of action of VCAN in HCC.
METHODS
Based on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we explored the correlation between VCAN expression and clinical features, and analyzed the prognosis of patients with high and low VCAN expression. The potential mechanism of action of VCAN was explored by Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis. We also explored immune cell infiltration, immune checkpoint gene expression, and sensitivity of immune checkpoint [programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte antigen 4 (CTLA4)] inhibitor therapy in patients with different VCAN expression. VCAN mRNA expression and VCAN methylation in peripheral blood were tested in 100 hepatitis B virus (HBV)-related patients (50 HCC and 50 liver cirrhosis).
RESULTS
VCAN was highly expressed in HCC tissues, which was associated with a poor prognosis in HCC patients. No significant difference was found in VCAN mRNA expression in blood between patients with HBV-related cirrhosis and those with HCC, but there was a significant difference in VCAN methylation between the two groups. The correlation between VCAN and infiltrations of several different tumor immune cell types (including B cells, CD8+ T cells, and eosinophils) was significantly different. VCAN was strongly related to immune checkpoint gene expression and tumor mutation burden, and could be a biomarker of sensitivity to immune checkpoint (PD1/CTLA4) inhibitors. In addition, VCAN mRNA expression was associated with hepatitis B e antigen, HBV DNA, white blood cells, platelets, cholesterol, and coagulation function.
CONCLUSION
High VCAN level could be a possible biomarker for poor prognosis of HCC, and its immunomodulatory mechanism in HCC warrants investigation.
Core Tip: VCAN expression is significantly higher in hepatocellular carcinoma (HCC) tumor tissue than in adjacent tissue, and high VCAN level may be a possible biomarker for the diagnosis and prognosis of HCC. VCAN is associated with hepatitis B e antigen in hepatitis B virus infected patients. VCAN may play a role in HCC through the extracellular matrix signaling pathway and inflammatory immune response, and is a potential biomarker for immune checkpoint (programmed cell death protein 1/cytotoxic T lymphocyte antigen 4) inhibitors.
