Research Paper Volume 13, Issue 17 pp 21216—21231

Dual roles of WISP2 in the progression of hepatocellular carcinoma: implications of the fibroblast infiltration into the tumor microenvironment

Qingan Jia1, , Yaoyao Zhang1, , Binghui Xu1, , Xia Liao2, , Yang Bu3, , Zihan Xu4, , Xianglong Duan5, , Qiangbo Zhang6,7, ,

  • 1 Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China
  • 2 Department of Nutrition, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
  • 3 Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan 750001, China
  • 4 Department of Burns and Plastic Surgery, Affiliated Shaanxi Provincial People’s Hospital, Northwestern Polytechnical University, Xi’an 710068, China
  • 5 Second Department of General Surgery, Shaanxi Provincial People's Hospital Affiliated Hospital of Northwestern Polytechnical University, Xi’an 710068, China
  • 6 Cheeloo College of Medicine, Shandong University, Jinan 250012, China
  • 7 Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China

Received: April 8, 2021       Accepted: July 8, 2021       Published: September 8, 2021
How to Cite

Copyright: © 2021 Jia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The dismal outcome of hepatocellular carcinoma (HCC) patients is attributable to high frequency of metastasis and. Identification of effective biomarkers is a key strategy to inform prognosis and improve survival. Previous studies reported inconsistent roles of WISP2 in carcinogenesis, while the role of WISP2 in HCC progression also remains unclear. In this study, we confirmed that WISP2 was downregulated in HCC tissues, and WISP2 was acting as a protective factor, especially in patients without alcohol intake using multiple online datasets. In addition, we reported that upregulation of WISP2 in HCC was related to inhibition of the malignant phenotype in vitro, but these alterations were not observed in vivo. WISP2 also negatively correlated with tumour purity, and increased infiltration of fibroblasts promoted malignant progression in HCC tissues. The enhanced infiltration ability of fibroblasts was related to upregulated HMGB1 after overexpression of WISP2 in HCC. The findings shed light on the anticancer role of WISP2, and HMGB1 is one of the key factors involved in the inhibition of the efficiency of WISP2 through reducing the tumour purity with fibroblast infiltration.


AJCC: American Joint Committee on Cancer; CCLE: Cancer Cell Line Encyclopedia; CCN: Cellular Communication Network; CM: Conditioned Medium; GEPIA2: Gene Expression Profiling Interactive Analysis 2; GO: Gene Ontology; HR: Hazard Ratio; HCC: Hepatocellular Carcinoma; HMGB1: High-Mobility Group Protein Box1; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIRC: Kidney Renal Clear Cell Carcinoma; KIRP: Kidney Renal Papillary Cell Carcinoma; PPI: Protein-Protein Interaction; TIMER: Tumor IMmune Estimation Resource; TME: Tumor Microenvironment; WISP2: WNT-1-Induced Signalling Protein-2.