Circular RNA SMAD4 coordinates with m6A‐dependent IGF2BP2 to promote gallbladder cancer development
5 affiliations
- 1Department of Biliary‐Pancreatic Surgery Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China
- 2Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation Jiading District Central Hospital Affiliated to Shanghai University of Medicine & Health Science Shanghai China
- 3Shanghai Cancer Institute State Key Laboratory of Systems Medicine for Cancer Shanghai China
- 4Department of Pathology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China
- 5Shanghai Key Laboratory of Biliary Tract Disease Research and Department of Surgery Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
Abstract
Circular RNAs (circRNAs) have emerged as important regulators in tumorigenesis through microRNA sponging, protein translation and interaction with RNA‐binding proteins. Here, we identified a novel circRNA termed circSMAD4 that was generated by alternative splicing from exon 2 to exon 10 and back to the beginning of exon 2 of SMAD4 pre‐mRNA, constituting a 1435‐nucleotide circular RNA. circSMAD4 was upregulated in gallbladder cancer (GBC) tissues and positively correlated with cancer progression. Elevated expression and tumorigenic activity of circSMAD4 mainly relied on its interaction with IGF2BP2, where m6A‐binding motifs located at KH3 and KH4 of IGF2BP2 recognized and bound to the flanking intron sequences of circSMAD4. In the cytoplasm, IGF2BP2 stabilized circSMAD4 levels, and circSMAD4 in turn inhibited ubiquitination and degradation of IGF2BP2, thereby creating a positive feedback loop for both elevated expressions. Collaboration of circSMAD4 and IGF2BP2 activated JAK2/STAT3 and epithelial–mesenchymal transition (EMT) signalling. Notably, treatment of xenografted mouse models with CWI1‐2, a small molecule for interruption of IGF2BP2 binding to circRNA, resulted in decreases in circSMAD4‐induced tumour development. Collectively, our findings suggest that circSMAD4 cooperates with IGF2BP2 to promote tumour progression, highlighting the circSMAD4‐IGF2BP2 complex as a potential therapeutic target in GBC.
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BibTeX
@article{li2026circular,
title = {{Circular RNA SMAD4 coordinates with m6A‐dependent IGF2BP2 to promote gallbladder cancer development}},
author = {Yiming Li and Yayun Xu and Yuan Zhang and Si Gao and Lili Gao and Zhiqing Yuan and Ziyi Wang and Shimei Qiu and Peipei Xu and Yuanding Liu and Zhaonan Liu and Huijie Miao and Hang Xu and Maolan Li and Rong Shao and Yingbin Liu},
journal = {Clinical and Translational Medicine},
year = {2026},
month = nov,
doi = {10.1002/ctm2.70892},
url = {https://doi.org/10.1002/ctm2.70892},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Circular RNA SMAD4 coordinates with m6A‐dependent IGF2BP2 to promote gallbladder cancer development
AU - Yiming Li
AU - Yayun Xu
AU - Yuan Zhang
AU - Si Gao
AU - Lili Gao
AU - Zhiqing Yuan
AU - Ziyi Wang
AU - Shimei Qiu
AU - Peipei Xu
AU - Yuanding Liu
AU - Zhaonan Liu
AU - Huijie Miao
AU - Hang Xu
AU - Maolan Li
AU - Rong Shao
AU - Yingbin Liu
PY - 2026
DA - 2026/11/05
JO - Clinical and Translational Medicine
DO - 10.1002/ctm2.70892
UR - https://doi.org/10.1002/ctm2.70892
AB - Circular RNAs (circRNAs) have emerged as important regulators in tumorigenesis through microRNA sponging, protein translation and interaction with RNA‐binding proteins. Here, we identified a novel circRNA termed circSMAD4 that was generated by alternative splicing from exon 2 to exon 10 and back to the beginning of exon 2 of SMAD4 pre‐mRNA, constituting a 1435‐nucleotide circular RNA. circSMAD4 was upregulated in gallbladder cancer (GBC) tissues and positively correlated with cancer progression. Elevated expression and tumorigenic activity of circSMAD4 mainly relied on its interaction with IGF2BP2, where m6A‐binding motifs located at KH3 and KH4 of IGF2BP2 recognized and bound to the flanking intron sequences of circSMAD4. In the cytoplasm, IGF2BP2 stabilized circSMAD4 levels, and circSMAD4 in turn inhibited ubiquitination and degradation of IGF2BP2, thereby creating a positive feedback loop for both elevated expressions. Collaboration of circSMAD4 and IGF2BP2 activated JAK2/STAT3 and epithelial–mesenchymal transition (EMT) signalling. Notably, treatment of xenografted mouse models with CWI1‐2, a small molecule for interruption of IGF2BP2 binding to circRNA, resulted in decreases in circSMAD4‐induced tumour development. Collectively, our findings suggest that circSMAD4 cooperates with IGF2BP2 to promote tumour progression, highlighting the circSMAD4‐IGF2BP2 complex as a potential therapeutic target in GBC.
SN - 2001-1326
ER -