Copyright
©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
IGF2BP3 binds to FBXO32 to activate the cyclic guanosine monophosphate-protein kinase G pathway, promoting gastric cancer progression
Yi Si, Bo Tian, Rui Zhang, Ming-Da Xuan, Kun-Yi Liu, Jiao Jiao, Shuang-Shuang Han, Hong-Fei Li, Yan-Hong Hu, Hong-Yan Zhao, Wen-Jing He, Jia Wang, Ting Liu, Wei-Fang Yu
Yi Si, Bo Tian, Rui Zhang, Ming-Da Xuan, Kun-Yi Liu, Jiao Jiao, Shuang-Shuang Han, Hong-Fei Li, Yan-Hong Hu, Ting Liu, Wei-Fang Yu, Gastrointestinal Disease Diagnosis and Treatment Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Hong-Yan Zhao, Wei-Fang Yu, Endoscopy Center, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Wen-Jing He, Endoscopy Center, Kuancheng Manchu Autonomous County Hospital, Chengde 067000, Hebei Province, China
Jia Wang, Department of Infectious Diseases, The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
Co-first authors: Yi Si and Bo Tian.
Co-corresponding authors: Ting Liu and Wei-Fang Yu.
Author contributions: Si Y, Tian B, Liu T, Yu WF designed the research study; Wang J, Liu T and Yu WF helped to supervised the study; Si Y, Tian B, Zhang R and Xuan MD performed most experiments, analyzed the data, wrote the manuscript and edited the paper; Liu KY, Jiao J and Han SS contributed to new reagents and analytic tools; Li HF, Hu YH, Zhao HY and He WJ helped to perform the experiments and analyzed the data; Liu T and Yu WF helped to edited the paper; all authors have read and approved the final manuscript.
Supported by the Hebei Natural Science Foundation, No. H2025206524, No. H2022206292 and No. H2024206140; Hebei Provincial Government-funded Provincial Medical Excellent Talent Project, No. ZF2023025, No. ZF2024134 and No. LS202008; Key RD Program of Hebei Province, No. 223777103D and No. 223777113D; Prevention and Treatment of Geriatric Diseases by Hebei Provincial Department of Finance, No. LNB202202 and No. LNB201909; Spark Scientific Research Project of the First Hospital of Hebei Medical University, No. XH202504, No. XH202312 and No. XH201805; and Hebei Province Medical Applicable Technology Tracking Project, No. G2019035.
Institutional review board statement: The study was approved by the Ethics Committee of the First Hospital of Hebei Medical University (approval No. S00112).
Institutional animal care and use committee statement: All animal experiments were approved by the Ethics Committee of the First Hospital of Hebei Medical University (approval No. S00111).
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: The data generated in this study are available upon request from the corresponding author.
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: Wei-Fang Yu, MD, Professor, Gastrointestinal Disease Diagnosis and Treatment Center, The First Hospital of Hebei Medical University, No. 89 Donggang Road, Shijiazhuang 050000, Hebei Province, China.
yuweifang@hebmu.edu.cn
Received: July 7, 2025
Revised: September 21, 2025
Accepted: October 24, 2025
Published online: December 14, 2025
Processing time: 158 Days and 6.8 Hours
BACKGROUND
N6-methyladenosine (m6A) exerts a pro-carcinogenic effect in diverse cancers. The relationship between m6A-reading protein IGF2BP3 and gastric cancer (GC) has not yet been fully elucidated.
AIM
To investigate the molecular mechanisms of IGF2BP3 in GC carcinogenesis and progression and thus provide a rationale for novel therapeutic strategies.
METHODS
Expression levels of IGF2BP3 in GC were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry, and their associations with patients’ clinicopathological characteristics were analyzed. The role of IGF2BP3 in GC was investigated using cellular functional assays and subcutaneous xenograft models, and its downstream targets and signaling pathways were identified using high-throughput sequencing, bioinformatics analysis, RNA immunoprecipitation qPCR, dual luciferase reporter assay, qRT-PCR, and WB. The mechanism of IGF2BP3 in GC was validated via WB and rescue and inhibition experiments.
RESULTS
IGF2BP3 was highly expressed in GC and associated with diffuse-type GC, incidence of lymph node metastasis, advanced tumor node metastasis stage, and deeper tumor invasion depth. In vitro experiments demonstrated that IGF2BP3 promoted proliferation, migration, and invasiveness of GC cells, while inhibiting apoptosis and augmenting intracellular levels of glucose metabolism. In vivo experiments revealed that IGF2BP3 contributes to the growth of GC. Mechanistically, IGF2BP3 recognized and bound to the m6A site at position 1427 on FBXO32 messenger RNA, thereby increasing protein expression of FBXO32, and further activated the downstream cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway to modulate various biological functions of GC cells and promote progression of GC. Furthermore, treatment with a selective PKG inhibitor KT5823 significantly suppressed the proliferative capacity of GC cells.
CONCLUSION
IGF2BP3 increases FBXO32 protein expression in an m6A-dependent manner, activates the cGMP-PKG signaling pathway, and promotes GC progression. Targeting of the IGF2BP3/FBXO32/cGMP-PKG axis could thus represent a promising therapeutic modality for GC.
Core Tip: IGF2BP3 is highly expressed in gastric cancer and is closely associated with poor patient prognosis. IGF2BP3 promotes gastric cancer growth and progression both in vivo and in vitro. Mechanistically, IGF2BP3 recognizes and binds to N6-methyladenosine-modified site on FBXO32 messenger RNA, thereby upregulating FBXO32 protein expression. This activates the downstream cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway, thereby regulating multiple biological functions of gastric cancer cells and promoting tumor progression. We propose that targeting of the IGF2BP3/FBXO32/cGMP-PKG axis could represent a promising therapeutic modality for gastric cancer.
