Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer.
Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer.
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DOI：
10.1016/j.jhep.2010.06.036
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发表时间：
2011-02
影响因子：
25.7
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
--
作者：
Calvisi DF;Ladu S;Conner EA;Seo D;Hsieh JT;Factor VM;Thorgeirsson SS
Ras通路的异常激活在人类肝癌发生中普遍存在，但在Ras突变缺失的情况下导致Ras诱导的分子机制尚不清楚。我们确定了Ras GTP酶激活蛋白（GAP）在人肝癌发生过程中Ras信号传导的组成性活性中的作用。在一组人肝细胞癌（HCC）中评估Ras基因和Ras效应子的突变状态。通过实时RT-PCR和免疫印迹测定Ras GAP（RASA 1 -4、RASAL 1、nGAP、SYNGAP 1、DAB 2 IP和NF 1）和RASAL 1上游诱导物PITX 1的水平。RASAL 1，DAB 2 IP，NF 1和PITX 1的启动子和基因组状态通过甲基化测定和微卫星分析进行评估。通过肝癌细胞系的转染和siRNA分析来评估RASAL 1、DAB 2 IP和PITX 1对肝癌生长的影响。在没有Ras突变的情况下，在所有HCC样品中发现至少一种Ras GAP（RASAL 1、DAB 2 IP或NF 1）的下调。低水平的DAB 2 IP和PITX 1主要在生存率低的HCC亚类中检测到，表明这些蛋白质控制肿瘤的侵袭性。在HCC细胞中，RASAL 1、DAB 2 IP和PITX 1的重新激活抑制增殖并诱导凋亡，而它们的沉默增加增殖和抗凋亡。选择性抑制RASAL 1、DAB 2 IP或NF 1 Ras GAP导致HCC中野生型Ras存在时Ras信号传导的不受限制的激活。
Aberrant activation of Ras pathway is ubiquitous in human hepatocarcinogenesis, but the molecular mechanisms leading to Ras induction in the absence of Ras mutations remain underinvestigated. We defined the role of Ras GTPase activating proteins (GAPs) in the constitutive activity of Ras signaling during human hepatocarcinogenesis. Mutation status of Ras genes and Ras effectors was assessed in a collection of human hepatocellular carcinoma (HCC). Levels of Ras GAPs (RASA1-4, RASAL1, nGAP, SYNGAP1, DAB2IP, and NF1) and the RASAL1 upstream inducer PITX1 were determined by real-time RT-PCR and immunoblotting. Promoter and genomic status of RASAL1, DAB2IP, NF1, and PITX1 were assessed by methylation assays and microsatellite analysis. Effects of RASAL1, DAB2IP, and PITX1 on HCC growth were evaluated by transfection and siRNA analyses of HCC cell lines. In the absence of Ras mutations, downregulation of at least one Ras GAP (RASAL1, DAB2IP, or NF1) was found in all HCC samples. Low levels of DAB2IP and PITX1 were detected mostly in a HCC subclass from patients with poor survival, indicating that these proteins control tumor aggressiveness. In HCC cells, reactivation of RASAL1, DAB2IP, and PITX1 inhibited proliferation and induced apoptosis, whereas their silencing increased proliferation and resistance to apoptosis. Selective suppression of RASAL1, DAB2IP, or NF1 Ras GAPs results in unrestrained activation of Ras signaling in the presence of wild-type Ras in HCC.
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影响因子：
--
作者：
Iwashita, Shintaro;Song, Si-Young
通讯作者：
Song, Si-Young
DOI：
10.1073/pnas.0700153104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Jin, Hongchuan;Wang, Xian;Tao, Qian
通讯作者：
Tao, Qian
影响因子：
4.8
作者：
Wang, Z;Tseng, CP;Hsieh, JT
通讯作者：
Hsieh, JT
影响因子：
56.9
作者：
LI, BQ;KAPLAN, D;KAMATA, T
通讯作者：
KAMATA, T
影响因子：
29.4
作者：
Ohta, Miki;Seto, Motoko;Omata, Masao
通讯作者：
Omata, Masao