Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis
Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis
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DOI：
10.1016/j.ccr.2004.11.024
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发表时间：
2005-01-01
期刊：
影响因子：
50.3
通讯作者：
Billadeau, DD
中科院分区：
文献类型：
--
作者：
Fernandez-Zapico, ME;Gonzalez-Paz, NC;Billadeau, DD
在此，我们发现造血特异性GEF VAV 1在原发性胰腺癌中异位表达是由于基因启动子的去甲基化。有趣的是，与VAV 1阴性肿瘤相比，VAV 1阳性肿瘤的存活率更低。令人惊讶的是，即使在致癌KRAS的存在下，VAV 1 RNAi在体外和体内消除肿瘤细胞增殖，从而将Vav 1鉴定为该疾病中的生长刺激蛋白。Vav 1与EGF受体协同作用，刺激胰腺肿瘤细胞增殖。从机制上讲，Vav 1的作用需要其GEF活性和Rac 1、PAK 1和NF-κ B的激活，并涉及细胞周期蛋白D1的上调。因此，发现由Vav 1调节的原癌途径使其成为治疗干预的有吸引力的靶点。
Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-KB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.