2. Academic Validation
  3. BUB1 potentiates gastric cancer proliferation and metastasis by activating TRAF6/NF-κB/FGF18 through m6A modification

BUB1 potentiates gastric cancer proliferation and metastasis by activating TRAF6/NF-κB/FGF18 through m6A modification

  • Life Sci. 2024 Jul 16:353:122916. doi: 10.1016/j.lfs.2024.122916.
Kun Wang 1,  Kanger Shen 1,  Jiayu Wang 2,  Kexi Yang 3,  Jinghan Zhu 4,  Yuqi Chen 5,  Xin Liu 2,  Yuxin He 3,  Xingchao Zhu 4,  Qin Zhan 3,  Tongguo Shi 6,  Rui Li 7
Affiliations

Affiliations

  • 1 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China; Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, China.
  • 2 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, China.
  • 4 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
  • 5 Department of Gastroenterology, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, China.
  • 6 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: shitg@suda.edu.cn.
  • 7 Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China; Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: lirui@suda.edu.cn.
PMID: 39025206 DOI: 10.1016/j.lfs.2024.122916
Abstract

Aims: Gastric Cancer (GC) is one of the most common malignant tumors of the digestive system. High expression of the mitotic kinase BUB1 has been shown to be associated with the development of many cancers, but the role of BUB1 in GC is still unclear. The current study aimed to investigate the role of BUB1 in GC.

Materials and methods: BUB1 inhibitor, siRNA or BUB1 overexpression plasmid-mediated functional studies were performed in vitro and in vivo to explore the oncogenic role of BUB1 in GC. The expression of BUB1 and FGF18 in GC tumor samples was determined by IHC staining. RNA-seq, Western blot, MeRIP-qPCR and Co-IP assays were used to investigate the molecular mechanisms by which BUB1 regulates GC progression.

Key findings: Knockdown of BUB1 significantly inhibited the proliferation and metastasis of GC cells in vitro and in vivo. Moreover, overexpression of BUB1 significantly promoted the proliferation, migration and invasion of GC cells. High expression of BUB1 and FGF18 in GC tissues predicted poor prognosis in GC patients. Mechanistically, BUB1 interacted with METTL3 and induced m6A modification of TRAF6 mRNA, further activating the NF-κB/FGF18 axis in GC cells.

Significance: Our results confirmed that BUB1 acts as a positive regulator of GC cell proliferation and metastasis by activating the TRAF6/NF-κB/FGF18 pathway through METTL3-mediated m6A methylation. Targeting the BUB1/METTL3/TRAF6/NF-κB/FGF18 axis might be a novel diagnostic and therapeutic strategy in GC.

Keywords

BUB1; FGF18; Gastric cancer; Metastasis; Proliferation; m6A modification.

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