title: P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway.
abstract: How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that the formation of vascular microthrombi contributes to tumor necrosis, prompting investigation of coagulation cascades. Here, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade in glioblastoma. P14ARF transcriptionally upregulated TFPI2, a Kunitz-type serine protease in the tissue factor pathway that inhibits the initiation of thrombosis reactions. P14ARF activation in tumor cells delayed their ability to activate plasma clotting. Mechanistically, P14ARF activated the TFPI2 promoter in a p53-independent manner that relied upon c-JUN, SP1, and JNK activity. Taken together, our results identify the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by glioma cells. Stimulation of this pathway might be used as a therapeutic strategy to reduce aggressive phenotypes associated with necrotic tumors, including glioblastoma.
authors.affiliation: Authors' Affiliations: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery; Departments of Pathology and Laboratory Medicine and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Abdessamad
authors.initials: A
authors.lastname: Zerrouqi
authors.forename: Beata
authors.initials: B
authors.lastname: Pyrzynska
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013925:Thromboplastin / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D025803:Tumor Suppressor Protein p14ARF; D013925:Thromboplastin