The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers
The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers
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DOI：
10.1038/nm1125
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发表时间：
2004-11-01
期刊：
影响因子：
82.9
通讯作者：
Mills, GB
中科院分区：
文献类型：
--
作者：
Cheng, KW;Lahad, JP;Mills, GB
高密度阵列比较基因组杂交(CGH)(1)显示，在大约一半的卵巢癌和乳腺癌中，染色体1q22的扩增集中在RAB25小GTP酶(2)上，该酶与顶端小泡运输有关(3)。与扩增区域内的其他基因相比，RAB25在III和IV期浆液性上皮性卵巢癌中的表达水平选择性地升高，这表明RAB25是扩增子发展的驱动事件。RAB25的DNA拷贝数或RNA水平的增加分别与卵巢癌和乳腺癌的无病生存率或总生存率显著降低相关。RAB25的强制表达显著增加了锚定依赖和非锚定依赖的细胞增殖，阻止了包括化疗在内的细胞凋亡和失巢，并增加了体内癌细胞的侵袭性。RAB25可能通过下调促凋亡分子BAK和Bax的表达，激活抗凋亡的磷脂酰肌醇3激酶(PI3K)和AKT通路来抑制肿瘤细胞的凋亡，为RAB25抑制肿瘤侵袭性提供了可能的机制。总体而言，这些研究表明RAB25，因此RAB家族的小G蛋白，与上皮性癌症的侵袭性有关。
High-density array comparative genomic hybridization (CGH)(1) showed amplification of chromosome 1q22 centered on the RAB25 small GTPase(2), which is implicated in apical vesicle trafficking(3), in approximately half of ovarian and breast cancers. RAB25 mRNA levels were selectively increased in stage III and IV serous epithelial ovarian cancers compared to other genes within the amplified region, implicating RAB25 as a driving event in the development of the amplicon. Increased DNA copy number or RNA level of RAB25 was associated with markedly decreased disease-free survival or overall survival in ovarian and breast cancers, respectively. Forced expression of RAB25 markedly increased anchorage-dependent and anchorage-independent cell proliferation, prevented apoptosis and anoikis, including that induced by chemotherapy, and increased aggressiveness of cancer cells in vivo. The inhibition of apoptosis was associated with a decrease in expression of the proapoptotic molecules, BAK and BAX, and activation of the antiapoptotic phosphatidylinositol 3 kinase (PI3K) and AKT pathway, providing potential mechanisms for the effects of RAB25 on tumor aggressiveness. Overall, these studies implicate RAB25, and thus the RAB family of small G proteins, in aggressiveness of epithelial cancers.