2. Academic Validation
  3. Succinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression

Succinylation Inhibits the Enzymatic Hydrolysis of the Extracellular Matrix Protein Fibrillin 1 and Promotes Gastric Cancer Progression

  • Adv Sci (Weinh). 2022 Sep;9(27):e2200546. doi: 10.1002/advs.202200546.
Xingyun Wang 1 2,  Xiao Shi 3,  Hongcheng Lu 4,  Chen Zhang 5,  Xiang Li 6,  Tiancheng Zhang 6,  Jiajia Shen 1,  Jianfei Wen 1
Affiliations

Affiliations

  • 1 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 2 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111, XianXia Road, Shanghai, 200336, China.
  • 3 Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
  • 4 Department of Urology, Zhongda Hospital Affiliated to Southeastern China University, Nanjing, 210029, China.
  • 5 Department of Biotherapy, Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
  • 6 Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
PMID: 35901491 DOI: 10.1002/advs.202200546
Abstract

Extracellular matrix (ECM) remodeling is crucial in the regulation of gastric Cancer (GC) progression. This work aims to reveal novel posttranslational modifications and their relevant mechanisms in GC. In 3D matrix culture and animal models, it is found that fibrillin 1 (FBN1) expression is increased in advanced GC and has succinylation modification. The succinylation modification of FBN1 blocks its degradation by Matrix Metalloproteinases (MMPs). The long-term accumulation and deposition of FBN1 enhance tumor progression by activating TGF-β1 and intracellular PI3K/Akt pathway. The FBN1 succinylation site monoclonal antibody can effectively intervene the effect of succinylation modification and inhibit GC progression. FBN1 is specifically upregulated in the progression of GC compared with other tumors. In conclusion, FBN1 is widely present in the form of K672-succinylated modifications in GC. Besides, the succinyl group of FBN1 blocks its binding to MMP2, inhibits its degradation by MMP2, and leads to the accumulation of FBN1, which poses a long-term risk to the poor prognosis of GC.

Keywords

MMP2; TGF-β1; fibrillin 1; gastric cancer; succinylation.

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