JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis

Journal of Experimental & Clinical Cancer Research

Chuan-Jun Shu¹  Dong-Yin Chen²  Yan-Lin Ren³  Min-Juan Chen³  Jun-Jie Chen³  Jian-Wei Zhou³  Yi Zhang³  Jin Xu³  Ai-Ping Li³  Jing-Dong He⁴  Jin Li⁴  Yong-Qian Shu⁵ 

[1] Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University;Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University;Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University;Department of Oncology, the affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University;Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University;

关键词: Targeting peptide;    JP3;    TRIM25;    SP1;    Ubiquitination;    Gastric cancer;   

DOI  :  10.1186/s13046-020-01617-8

来源: DOAJ

【 摘 要 】

Abstract Background Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer. Methods Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2. Results We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients. Conclusions MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.

【 授权许可】

Unknown