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.
Cancer Res. 2014 Mar 1;74(5):1371-8. doi: 10.1158/0008-5472.CAN-13-1951. Epub 2014 Jan 7.
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.
肿瘤中坏死区域的形成机制尚不完全清楚，但可能会影响肿瘤的进展。最近的研究结果表明，血管微血栓的形成可能导致肿瘤坏死，促使人们对凝血级联反应进行研究。在这里，我们报告称，肿瘤抑制因子 P14ARF 的缺失可能有助于激活胶质母细胞瘤中的凝血级联反应。P14ARF 转录上调 TFPI2，TFPI2 是组织因子途径中的一种 Kunitz 型丝氨酸蛋白酶，可抑制血栓反应的起始。肿瘤细胞中 P14ARF 的激活延迟了其激活血浆凝固的能力。从机制上讲，P14ARF 以一种不依赖 p53 的方式激活 TFPI2 启动子，该方式依赖于 c-JUN、SP1 和 JNK 的活性。总之，我们的研究结果确定了 P14ARF 激活的关键信号通路，可防止由神经胶质瘤细胞引发的血管微血栓形成。刺激该通路可能被用作一种治疗策略，以减少与坏死肿瘤相关的侵袭性表型，包括胶质母细胞瘤。
