P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway.
P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway.
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DOI：
10.1158/0008-5472.can-13-1951
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Van Meir EG
中科院分区：
文献类型：
--
作者：
Zerrouqi A;Pyrzynska B;Brat DJ;Van Meir EG
肿瘤坏死区域如何发展尚不完全清楚，但会影响进展。最近的研究结果表明，血管微血栓的形成有助于肿瘤坏死，促使对凝血级联反应的研究。在这里，我们报道肿瘤抑制因子p14ARF的缺失可以激活胶质母细胞瘤（GBM）中的凝血级联反应。p14ARF通过转录上调TFPI2， TFPI2是一种在组织因子通路中抑制血栓形成反应的kuniz型丝氨酸蛋白酶。p14ARF在肿瘤细胞中的激活延迟了它们激活血浆凝血的能力。机制上，p14ARF以p53独立的方式激活TFPI2启动子，依赖于c-JUN、SP1和JNK活性。综上所述，我们的研究结果确定了p14ARF激活的关键信号通路，以防止胶质瘤细胞引发的血管微血栓形成。刺激这一途径可能作为一种治疗策略，以减少与坏死肿瘤（包括胶质母细胞瘤）相关的侵袭性表型。
How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that 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 (GBM). 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.