Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer
Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer
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DOI：
10.1038/onc.2012.101
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发表时间：
2013-02-14
期刊：
影响因子：
8
通讯作者：
Horiuchi, H.
中科院分区：
文献类型：
--
作者：
Saito, R.;Shirakawa, R.;Horiuchi, H.
已知小的GTdR α 1在几种人类癌症中高度活化，例如膀胱癌、结肠癌和胰腺癌。研究发现，活化的Ral参与了膀胱癌细胞的增殖、迁移和转移。这种蛋白质被Ral鸟嘌呤核苷酸交换因子（RaIGEF）激活，并被大鼠GTP酶激活蛋白（RaIGAP）灭活，后者由含有催化α 1或α 2亚基和共同β亚基的异二聚体组成。在Ras驱动的癌症中，如胰腺癌和结肠癌，组成型活性Ras突变体通过与RaIGEF相互作用激活Ral，RaIGEF含有Ras缔合结构域。然而，关于膀胱癌中Ral异常激活的机制知之甚少，其中Ras突变相对罕见。在这里，我们表明，由于RaIGAP α 2（膀胱中的主要催化亚基）表达减少，而不是RaIGEFs表达增加，Ral在浸润性膀胱癌细胞中被高度激活。在具有侵袭性表型的KU 7膀胱癌细胞中外源表达野生型RaIGAP α 2，而不是缺乏RaIGAP活性的突变体RaIGAID α 2-N1742 K，导致体外细胞迁移和体内肺转移减弱。此外，在化学诱导的小鼠膀胱癌模型中，Ralgapa 2的基因消融促进了肿瘤侵袭。重要的是，对人类膀胱癌标本的免疫组化分析表明，RaIGAP α 2的低表达与患者的临床分期晚期和生存率低有关。总的来说，这些结果高度指示RaIGAP α 2的减弱表达通过增强Ral活性导致膀胱癌的疾病进展。Oncogene（2013）32，894-902; doi：10.1038/onc.2012.101; 2012年3月26日在线发表
The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RaIGEFs) and inactivated by Rat GTPase-activating proteins (RaIGAPs), the latter of which consist of heterodimers containing a catalytic alpha 1 or alpha 2 subunit and a common beta subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RaIGEFs, which contain the Ras association domain. However, little is known with regard to the mechanism that governs aberrant activation of Ral in bladder cancer, in which Ras mutations are relatively infrequent. Here, we show that Ral was highly activated in invasive bladder cancer cells due to reduced expression of RaIGAP alpha 2, the dominant catalytic subunit in bladder, rather than increased expression of RaIGEFs. Exogenous expression of wild-type RaIGAP alpha 2 in KU7 bladder cancer cells with invasive phenotype, but not mutant RaIGAID alpha 2-N1742K lacking RaIGAP activity, resulted in attenuated cell migration in vitro and lung metastasis in vivo. Furthermore, genetic ablation of Ralgapa2 promoted tumor invasion in a chemically-induced murine bladder cancer model. Importantly, immunohistochennical analysis of human bladder cancer specimens revealed that lower expression of RaIGAP alpha 2 was associated with advanced clinical stage and poor survival of patients. Collectively, these results are highly indicative that attenuated expression of RaIGAP alpha 2 leads to disease progression of bladder cancer through enhancement of Ral activity. Oncogene (2013) 32, 894-902; doi:10.1038/onc.2012.101; published online 26 March 2012