2. Academic Validation
  3. N6-methyladenosine modified circPAK2 promotes lymph node metastasis via targeting IGF2BPs/VEGFA signaling in gastric cancer

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

  • Oncogene. 2024 Jul 17. doi: 10.1038/s41388-024-03099-w.
Ping'an Ding # 1 2 3,  Haotian Wu # 1 2 3,  Jiaxiang Wu # 1 2 3,  Tongkun Li 1 2 3,  Jinchen He 1 2 3,  Yingchao Ju 2 3 4,  Yueping Liu 2 3 5,  Fang Li 2 3 5,  Huiyan Deng 2 3 5,  Renjun Gu 6 7,  Lilong Zhang 8,  Honghai Guo 1 2 3,  Yuan Tian 1 2 3,  Peigang Yang 1 2 3,  Ning Meng 9,  Xiaolong Li 10,  Zhenjiang Guo 11,  Lingjiao Meng 12,  Qun Zhao 13 14 15
Affiliations

Affiliations

  • 1 The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
  • 2 Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, Hebei, China.
  • 3 Big data analysis and mining application for precise diagnosis and treatment of gastric cancer Hebei Provincial Engineering Research Center, Shijiazhuang, Hebei, China.
  • 4 Animal Center of the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
  • 5 Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
  • 6 School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 7 Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
  • 8 Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
  • 9 Department of General Surgery, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China.
  • 10 Department of General Surgery, Baoding Central Hospital, Baoding, Hebei, China.
  • 11 General Surgery Department, Hengshui People's Hospital, Hengshui, Hebei, China.
  • 12 Research Center and Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. ljmeng@hebmu.edu.cn.
  • 13 The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. zhaoqun@hebmu.edu.cn.
  • 14 Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, Hebei, China. zhaoqun@hebmu.edu.cn.
  • 15 Big data analysis and mining application for precise diagnosis and treatment of gastric cancer Hebei Provincial Engineering Research Center, Shijiazhuang, Hebei, China. zhaoqun@hebmu.edu.cn.
  • # Contributed equally.
PMID: 39014193 DOI: 10.1038/s41388-024-03099-w
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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