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N6-methyladenosine modified circPAK2 promotes lymph node metastasis via targeting IGF2BPs/VEGFA signaling in gastric cancer

Oncogene volume 43, pages 2548–2563 (2024)Cite this article

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Abstract

Circular RNAs (circRNAs) have emerged as key regulators of cancer occurrence and progression, as well as promising biomarkers for cancer diagnosis and prognosis. However, the potential mechanisms of circRNAs implicated in lymph node (LN) metastasis of gastric cancer remain unclear. Herein, we identify a novel N6-methyladenosine (m6A) modified circRNA, circPAK2, which is significantly upregulated in gastric cancer tissues and metastatic LN tissues. Functionally, circPAK2 enhances the migration, invasion, lymphangiogenesis, angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis of gastric cancer in vitro and in vivo. Mechanistically, circPAK2 is exported by YTH ___domain-containing protein 1 (YTHDC1) from the nucleus to the cytoplasm in an m6A methylation-dependent manner. Moreover, increased cytoplasmic circPAK2 interacts with Insulin-Like Growth Factor 2 mRNA-Binding Proteins (IGF2BPs) and forms a circPAK2/IGF2BPs/VEGFA complex to stabilize VEGFA mRNA, which contributes to gastric cancer vasculature formation and aggressiveness. Clinically, high circPAK2 expression is positively associated with LN metastasis and poor prognosis in gastric cancer. This study highlights m6A-modified circPAK2 as a key regulator of LN metastasis of gastric cancer, thus supporting circPAK2 as a promising therapeutic target and prognostic biomarker for gastric cancer.

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Fig. 1: Characteristics of circPAK2 in gastric cancer cells and tissues.
Fig. 2: CircPAK2 enhances the migration, invasion, EMT, lymphangiogenesis, angiogenesis and metastasis of gastric cancer in vitro and in vivo.
Fig. 3: CircPAK2 is exported by YTHDC1 from nucleus to cytoplasm in an m6A-dependent manner.
Fig. 4: CircPAK2 interacts with IGF2BP1/2/3 in an m6A-dependent manner.
Fig. 5: CircPAK2/IGF2BPs/VEGFA complex stabilizes VEGFA mRNA.
Fig. 6: CircPAK2 promotes LN metastasis of gastric cancer through targeting VEGFA.
Fig. 7: Clinical validation process of circPAK2 as a biomarker for LN metastasis and prognosis prediction of gastric cancer.
Fig. 8

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Data availability

The processed data in this study have been deposited in GEO under accession number GSE248612.

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Acknowledgements

This work was supported by grants from the Hebei Provincial Major Science and Technology Special Project (23297701Z), Beijing–Tianjin–Hebei Basic Research Cooperation Special Project (22JCZXJC00140), and Hebei Provincial Government-funded Clinical Talent Project (ZF2023047).

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Author notes

  1. These authors contributed equally: Ping’an Ding, Haotian Wu, Jiaxiang Wu.

Authors and Affiliations

  1. The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Ping’an Ding, Haotian Wu, Jiaxiang Wu, Tongkun Li, Jinchen He, Honghai Guo, Yuan Tian, Peigang Yang & Qun Zhao

  2. Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, Hebei, China

    Ping’an Ding, Haotian Wu, Jiaxiang Wu, Tongkun Li, Jinchen He, Yingchao Ju, Yueping Liu, Fang Li, Huiyan Deng, Honghai Guo, Yuan Tian, Peigang Yang & Qun Zhao

  3. Big data analysis and mining application for precise diagnosis and treatment of gastric cancer Hebei Provincial Engineering Research Center, Shijiazhuang, Hebei, China

    Ping’an Ding, Haotian Wu, Jiaxiang Wu, Tongkun Li, Jinchen He, Yingchao Ju, Yueping Liu, Fang Li, Huiyan Deng, Honghai Guo, Yuan Tian, Peigang Yang & Qun Zhao

  4. Animal Center of the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Yingchao Ju

  5. Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Yueping Liu, Fang Li & Huiyan Deng

  6. School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

    Renjun Gu

  7. Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Renjun Gu

  8. Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Lilong Zhang

  9. Department of General Surgery, Shijiazhuang People’s Hospital, Shijiazhuang, Hebei, China

    Ning Meng

  10. Department of General Surgery, Baoding Central Hospital, Baoding, Hebei, China

    Xiaolong Li

  11. General Surgery Department, Hengshui People’s Hospital, Hengshui, Hebei, China

    Zhenjiang Guo

  12. Research Center and Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Lingjiao Meng

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Contributions

Study concept and design: DPA, MLJ, ZQ; Specimen collection: DPA, WHT, WJX, LTK, HJC, GRJ, ZLL, GHH, TY, YPG, MN, LXL, GZJ; Acquisition of clinical data: DPA, LTK, HJC, GRJ, ZLL, GHH, TY, YPG, MN, LXL, GZJ; Cell biology experiments: WHT and WJX; Animal experiments: DPA, WHT, JYC; Interpretation of pathological sections: LF, DHY, LYP; Data organization and statistical analysis: DPA and MLJ; Drafting of the manuscript: DPA and MLJ; Correction and review of the manuscript: ZQ and MLJ.

Corresponding authors

Correspondence to Lingjiao Meng or Qun Zhao.

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This multicenter study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board of the Fourth Hospital of Hebei Medical University and all other participating hospitals (Ethics Approval Number: 2023KY139). All authors followed the applicable ethical standards to maintain research integrity without any duplication, fraud, or plagiarism issues. Informed consent was obtained from all subjects for this study.

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Ding, P., Wu, H., Wu, J. et al. N6-methyladenosine modified circPAK2 promotes lymph node metastasis via targeting IGF2BPs/VEGFA signaling in gastric cancer. Oncogene 43, 2548–2563 (2024). https://doi.org/10.1038/s41388-024-03099-w

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