Zhang XZ, Mo XC, Wang ZT, Sun R, Sun DQ. N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway. World J Gastrointest Oncol 2024; 16(6): 2769-2780 [PMID: 38994173 DOI: 10.4251/wjgo.v16.i6.2769]
Corresponding Author of This Article
Da-Quan Sun, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Ankang Avenue, Machang Town, Guian New District, Guiyang 550025, Guizhou Province, China. sundq04@sina.com
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Biochemistry & Molecular Biology
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Basic Study
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Zhang XZ, Mo XC, Wang ZT, Sun R, Sun DQ. N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway. World J Gastrointest Oncol 2024; 16(6): 2769-2780 [PMID: 38994173 DOI: 10.4251/wjgo.v16.i6.2769]
World J Gastrointest Oncol. Jun 15, 2024; 16(6): 2769-2780 Published online Jun 15, 2024. doi: 10.4251/wjgo.v16.i6.2769
N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway
Xin-Zhan Zhang, Xiao-Chuan Mo, Zhu-Ting Wang, Rong Sun, Da-Quan Sun
Xin-Zhan Zhang, Xiao-Chuan Mo, Zhu-Ting Wang, Rong Sun, Da-Quan Sun, Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
Author contributions: Zhang XZ, Sun DQ, Mo XC, Wang ZT, Sun R contributed to the conception of the study; Zhang XZ performed the experiment; Zhang XZ, Mo XC contributed significantly to analysis and manuscript preparation; Zhang XZ, Sun DQ performed the data analyses and wrote the manuscript; Zhang XZ, Sun DQ, Mo XC, Wang ZT, Sun R helped perform the analysis with constructive discussions.
Supported byNational Natural Science Foundation of China, No. 81560390; the Guizhou Medical University Cultivation Project of the National Natural Science Foundation of China, No. 22NSFCP02; and Basic Research Project of Science and Technology Department of Guizhou Province, No. ZK[2024] General 136.
Institutional animal care and use committee statement: The study was reviewed and approved by the Animal Care Welfare Committee of Guizhou Medical University.
Conflict-of-interest statement: Dr. Sun has nothing to disclose.
Data sharing statement: No data available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Da-Quan Sun, PhD, Assistant Professor, Department of Biochemistry and Molecular Biology & Research Center for Basic Medical Sciences, Guizhou Medical University, Ankang Avenue, Machang Town, Guian New District, Guiyang 550025, Guizhou Province, China. sundq04@sina.com
Received: March 7, 2024 Revised: April 25, 2024 Accepted: April 28, 2024 Published online: June 15, 2024 Processing time: 99 Days and 16.8 Hours
Abstract
BACKGROUND
Wnt/FZD-mediated signaling pathways are activated in more than 90% of hepatocellular carcinoma (HCC) cell lines. As a well-known secretory glycoprotein, Wnt3 can interact with FZD receptors on the cell surface, thereby activating the Wnt/β-catenin signaling pathway. However, the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still unclear.
AIM
To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC cells.
METHODS
Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites, actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation, the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy, and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function experiments.
RESULTS
Wnt3 has two N-glycosylation-modified sites (Asn90 and Asn301); when a single site at amino acid 301 is mutated, the stability of Wnt3 is weakened; the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously; and the level of proteins related to the Wnt/β-catenin signaling pathway is downregulated. Cell proliferation, migration and invasion are also weakened in the case of single 301 site and double-site mutations.
CONCLUSION
These results indicate that by inhibiting the N-glycosylation of Wnt3, the proliferation, migration, invasion and colony formation abilities of liver cancer cells can be weakened, which might provide new therapeutic strategies for clinical liver cancer in the future.
Core Tip: Our study reveals that Wnt3 undergoes N-glycosylation modification at two specific sites (Asn90 and Asn301). Mutation of these sites impairs the stability and function of Wnt3, reducing its binding ability to FZD7 and downregulating the Wnt/β-catenin signaling pathway. Consequently, cell proliferation, migration, and invasion are attenuated in hepatocellular carcinoma cells. These findings suggest that targeting Wnt3 N-glycosylation could be a potential therapeutic strategy for liver cancer.
