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Publication Name
World Journal of Gastroenterology
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1007-9327
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study
Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Gastroenterol. Sep 21, 2026; 32(35): 121494
Published online Sep 21, 2026. doi: 10.3748/wjg.121494
Tn antigen-driven downregulation of podoplanin promotes colorectal cancer invasion
Li-Wen Fan, Xin-Zhe Wu, Zi-Wei Liu, Qi Lin, Jia-Xin Du, Yan-Tao Tian, Xi-Chen Dong, Dong-Kui Xu
Li-Wen Fan, Qi Lin, Jia-Xin Du, School of Clinical Medicine, The Hebei University of Engineering, Handan 056000, Hebei Province, China
Xin-Zhe Wu, Zi-Wei Liu, Xi-Chen Dong, Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100021, China
Yan-Tao Tian, Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Dong-Kui Xu, Department of Very Important Person, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Co-corresponding authors: Xi-Chen Dong and Dong-Kui Xu.
Author contributions: Fan LW performed the experiments and wrote the original manuscript; Wu XZ performed the analysis of single-cell RNA sequencing data; Liu ZW conducted parts of the experimental work; Lin Q and Du JX contributed to data analysis; Dong XC was responsible for overall study design and supervision; Tian YT was primarily responsible for data collection; Xu KD as the principal investigator of the project, was responsible for the overall design and strategic direction of the study, providing framing the key scientific questions, participated in the design of validation of critical methodologies, and the construction of the analytical framework for the results, offered crucial feedback on the scientific logic, data interpretation, and conclusion development of the manuscript, and performed comprehensive review, revision, and final approval of the submitted work.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by the National High Level Hospital Clinical Research Funding; and National Natural Science Foundation of China, No. 82372989.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: All animal experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (approval No. NCC2023A165).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. The public dataset used in this study is available in the Gene Expression Omnibus repository under accession number GSE132465.
Corresponding author: Dong-Kui Xu, MD, Professor, Department of Very Important Person, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. 13691583382@163.com
Received: March 27, 2026
Revised: May 9, 2026
Accepted: June 18, 2026
Published online: September 21, 2026
Processing time: 143 Days and 12.3 Hours
Abstract
BACKGROUND

Colorectal cancer (CRC) is the third most common malignant tumor and the second leading cause of cancer-related death worldwide. Abnormal O-glycosylation of proteins are a significant molecular feature of CRC, with high Tn antigen expression closely associated with tumor invasion and metastasis. Podoplanin (PDPN) is a highly O-glycosylated transmembrane mucin that is aberrantly expressed in various tumors, but its specific function in CRC remains incompletely understood.

AIM

To investigate the functional role of abnormally O-glycosylated PDPN (marked by Tn antigen expression) in CRC.

METHODS

In this study, clustered regularly interspaced short palindromic repeats associated protein 9 technology was used to knock out the C1GALT1 gene in CRC cells. Wild-type-PDPN and O-glycosylation-mutated (mu-PDPN) overexpression vectors were constructed. Cell counting kit-8 and Transwell assays were used to evaluate cell proliferation and migration capabilities, while western blotting was performed to detect the expression of epithelial-mesenchymal transition (EMT)-related markers. A nude mouse subcutaneous xenograft model was established to evaluate tumor growth in vivo, and immunohistochemistry was used to detect Ki67 expression. Furthermore, single-cell RNA sequencing data were obtained from the Gene Expression Omnibus database (GSE132465).

RESULTS

High expression of the Tn antigen was detected in CRC tissue samples. Compared with that in the control group, high Tn antigen expression induced by C1GALT1 knockout significantly increased the proliferation and migration capabilities of cancer cells, accompanied by a decrease in PDPN protein levels. Functionally, the overexpression of PDPN effectively inhibited cell proliferation and migration, whereas the overexpression of mu-PDPN lost this tumor-suppressive effect. Furthermore, mu-PDPN induced the upregulation of vimentin and Snail expression and the downregulation of E-cadherin and zonula occludens-1 expression during EMT. In vivo experiments further confirmed that mu-PDPN promoted the growth of mouse xenograft tumors and increased the percentage of Ki67-positive tumor cells. Bioinformatic analysis revealed a significant positive correlation between C1GALT1 and PDPN messenger RNA expression in CRC patients.

CONCLUSION

The tumor-suppressive function of PDPN depends strictly on its intact O-glycosylation. When abnormal O-glycan synthesis leads to Tn antigen exposure, PDPN loses its ability to inhibit tumor cell proliferation and migration and may promote CRC progression by activating the EMT pathway.

Keywords: Colorectal cancer; O-glycosylation; Podoplanin; T-synthase; C1GALT1

Core Tip: This study is the first to report that the tumor-suppressive function of the key glycoprotein podoplanin (PDPN) depends strictly on its intact O-glycosylation. When T-synthase deficiency leads to Tn antigen exposure, abnormal PDPN O-glycosylation occurs, resulting in decreased protein stability and functional loss, thereby abolishing the inhibitory effects of PDPN on cell proliferation and migration. These findings provide a new theoretical foundation for the use of glycosylation-dependent PDPN as a prognostic biomarker and targeted therapeutic strategy.
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