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

J Exp Clin Cancer Res. 2020 Jun 23;39(1):118. doi: 10.1186/s13046-020-01617-8.


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.

Keywords: Angiogenesis; Experimental therapy; Gastric cancer; JP3; SP1; TRIM25; Targeting peptide; Ubiquitination.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Movement
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Peptide Fragments / pharmacology*
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism*
  • Tumor Cells, Cultured
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Peptide Fragments
  • Sp1 Transcription Factor
  • Sp1 protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases
  • MMP2 protein, human
  • Matrix Metalloproteinase 2