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. 2024 Aug;43(34):2548-2563.
doi: 10.1038/s41388-024-03099-w. Epub 2024 Jul 17.

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

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

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

Ping'an Ding et al. Oncogene. 2024 Aug.

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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