IGF2BP3 binds to FBXO32 to activate the cyclic guanosine monophosphate-protein kinase G pathway - promoting gastric cancer progression

Sep 23, 2026

Background: N6-methyladenosine (m6A) promotes tumorigenesis, yet how the m6A-reading protein IGF2BP3 relates to gastric cancer remains incompletely defined. Aim: Clarify IGF2BP3’s molecular mechanisms in gastric cancer carcinogenesis and progression and support rationale for novel therapies. Methods: IGF2BP3 expression was assessed by qRT-PCR, western blot, and immunohistochemistry; cellular functional assays, xenografts, and pathway target analyses were performed. Results: IGF2BP3 was elevated and linked to aggressive disease, enhancing proliferation, migration, invasion, and metabolic glucose activity while suppressing apoptosis. Mechanistically, IGF2BP3 binds m6A on FBXO32 mRNA, increases FBXO32 protein, and activates cGMP-PKG signaling; PKG inhibitor KT5823 reduced growth. Conclusion: Targeting the IGF2BP3/FBXO32/cGMP-PKG axis may offer therapeutic value.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages26

Reading Time1 h 6 min

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Background

Aim

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Conclusion

| W | J | G | World Journal of
Gastroenterology | | --- | --- | --- | --- | Submit a Manuscript: [https://www.f6publishing.com](https://www.f6publishing.com) World J Gastroenterol 2025 December 14; 31(46): 111631 DOI: 10.3748/wjg.v31.i46.111631 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Basic Study 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 Specialty type: Gastroenterology and hepatology Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review report’s classification Scientific Quality: Grade A, Grade A, Grade B Novelty: Grade A, Grade B, Grade B Creativity or Innovation: Grade B, Grade B, Grade B Scientific Significance: Grade A, Grade A, Grade B P-Reviewer: An XD, PhD, China; Inam S, PhD, Assistant Professor, Pakistan; Xie Y, PhD, China Received: July 7, 2025 Revised: September 21, 2025 Accepted: October 24, 2025 Published online: December 14, 2025 Processing time: 158 Days and 5.9 Hours 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. 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.](China. yuweifang@hebmu.edu.cn)[ yuweifang@hebmu.edu.cn](China. yuweifang@hebmu.edu.cn) Abstract 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 WJG [https://www.wjgnet.com](https://www.wjgnet.com) 1 December 14, 2025 Volume 31 Issue 46 Si Y et al. IGF2BP3 promotes GC by targeting FBXO32/cGMP-PKG 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 highthroughput 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 reve

FAQs

What central role does IGF2BP3 play in gastric cancer progression?

IGF2BP3 is highly expressed in gastric cancer and promotes proliferation, migration, invasiveness, and glucose metabolism while inhibiting apoptosis, contributing to tumor growth in vitro and in vivo.

How does IGF2BP3 regulate its downstream pathway at the molecular level?

IGF2BP3 recognizes and binds an m6A site on FBXO32 mRNA, increases FBXO32 protein expression, and activates the cGMP-PKG signaling pathway that drives multiple GC cell biological functions.

What evidence supports the importance of cGMP-PKG signaling?

Treatment with the selective PKG inhibitor KT5823 significantly suppresses the proliferative capacity of gastric cancer cells, supporting that cGMP-PKG activity is functionally important.

Sep 23, 2026

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