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IGF2BP1 promotes gastric cancer progression by stabilizing HS6ST2 mRNA in an N6-methyladenosine-dependent manner
Lu Liu, Yi-Jing Zhou, Yue Xu, Qian-Qian Yin, Jue-Jue Wang, Shan-Jing Xu, Ling-Ling Yan, Zhen-Zhen Wang, Shao-Wei Li, Xin-Li Mao, Yu Zhang
Lu Liu, Yi-Jing Zhou, Qian-Qian Yin, Jue-Jue Wang, Shan-Jing Xu, Ling-Ling Yan, Zhen-Zhen Wang, Shao-Wei Li, Xin-Li Mao, Yu Zhang, Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
Yue Xu, Xin-Li Mao, Yu Zhang, Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Shaoxing University, Linhai 317000, Zhejiang Province, China
Shao-Wei Li, Xin-Li Mao, Yu Zhang, Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, Linhai 317000, Zhejiang Province, China
Co-corresponding authors: Xin-Li Mao and Yu Zhang.
Author contributions: Liu L performed most of the experiments and statistical analyses; Liu L and Zhou YJ drafted the manuscript; Liu L and Li SW conceived and designed the study; Zhou YJ, Yin QQ, and Wang JJ assisted in the experiments; Xu Y contributed to the performance of statistical analyses; Xu SJ, Yan LL, and Wang ZZ collected the clinical samples; Mao XL and Zhang Y provided administrative, technical, material support, and they will serve as co-corresponding authors, sharing the responsibility for all correspondence, oversight, and post-publication investigatory activities related to the study. All authors critically reviewed and revised the manuscript and approved the final version for publication.
Supported by National Natural Science Foundation of China, No. 82570702; “Pioneer” and “Leading Goose” Research and Development Program of Zhejiang, No. 2025C02139; Zhejiang Clinovation Pride, No. CXTD202502030; Medical Science and Technology Project of Zhejiang Province, No. 2025KY1818 and 2023KY1312; Science and Technology Plan Project of Taizhou, No. 22ywb09; and the Major Projects of Taizhou Enze Medical Center, No. 2025EZZD02.
Institutional review board statement: Ethics approval for this study was obtained from the Medical Ethics Committee of Taizhou Hospital (Approval No. K20201205).
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of Taizhou Enze Medical Center (Group) (Approval No. tzy-2023198).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Further information and requests for resources should be directed to and will be fulfilled by corresponding author.
Corresponding author: Yu Zhang, MD, Chief Physician, Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No. 150 Ximen Street, Linhai 317000, Zhejiang Province, China.
zy@enzemed.com
Received: February 6, 2026
Revised: February 28, 2026
Accepted: April 14, 2026
Published online: July 15, 2026
Processing time: 150 Days and 15.9 Hours
BACKGROUND
Gastric cancer (GC) remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis, which highlights an urgent need to identify effective biomarkers and therapeutic targets. N6-methyladenosine (m6A) modification and its reader proteins play a crucial role in tumorigenesis. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) participates in carcinogenesis and serves as a reader of m6A. However, its exact function and the underlying molecular mechanisms in the progression of GC remain unknown.
AIM
To investigate the role of IGF2BP1 in the progression of GC.
METHODS
The IGF2BP1 expression in GC tissues was assessed via immunohistochemistry and correlated with clinicopathological characteristics. Gain-of-function and loss-of-function experiments were performed to explore the functional roles of IGF2BP1 and its potential downstream target in GC cells and a nude mouse xenograft model. Cell proliferation, migration, and invasion were assessed using cell counting kit-8, wound-healing, and Transwell assays. RNA sequencing, methylated RNA immunoprecipitation quantitative polymerase chain reaction, and dual-luciferase reporter assays were conducted to elucidate the molecular mechanisms involved.
RESULTS
The IGF2BP1 was significantly upregulated in GC tissues and was positively associated with lymph node metastasis and poor overall survival. Functionally, IGF2BP1 knockdown inhibited GC cell proliferation, migration, and invasion in vitro and attenuated tumor growth in vivo. Integrated multi-omics analysis identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a key downstream target of IGF2BP1. IGF2BP1 recognized and bound to m6A-modified sites within HS6ST2 mRNA, thereby enhancing its stability in an m6A-dependent manner. Rescue experiments confirmed that HS6ST2 mediated the oncogenic effects of IGF2BP1. Additionally, HS6ST2 knockdown inhibited the malignant characteristics of GC cells and triggered apoptosis, which was associated with inactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.
CONCLUSION
These findings demonstrated that IGF2BP1 drives GC progression by stabilizing HS6ST2 mRNA via m6A modification. The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic intervention for GC.
Core Tip: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an N6-methyladenosine reader that is highly expressed in gastric cancer (GC) and is associated with lymph node metastasis and poor prognosis. This study elucidates the oncogenic mechanism of IGF2BP1 via its downstream target, heparan sulfate 6-O-sulfotransferase 2 (HS6ST2). Both in vitro and in vivo analyses demonstrate that IGF2BP1 stabilizes HS6ST2 mRNA in an N6-methyladenosine-dependent manner, which, in turn, activates the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway, thereby driving GC cell proliferation, invasion, and metastasis. Taken together, these results may identify the IGF2BP1/HS6ST2 axis as a potential prognostic biomarker and therapeutic target in GC.
