Pivotal role of mTOR signaling in hepatocellular carcinoma.
Pivotal role of mTOR signaling in hepatocellular carcinoma.
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DOI：
10.1053/j.gastro.2008.08.008
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发表时间：
2008-12
期刊：
影响因子：
29.4
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Villanueva A;Chiang DY;Newell P;Peix J;Thung S;Alsinet C;Tovar V;Roayaie S;Minguez B;Sole M;Battiston C;Van Laarhoven S;Fiel MI;Di Feo A;Hoshida Y;Yea S;Toffanin S;Ramos A;Martignetti JA;Mazzaferro V;Bruix J;Waxman S;Schwartz M;Meyerson M;Friedman SL;Llovet JM
肝细胞癌（HCC）靶向治疗的出现强调了通路特征描述对于确定新型治疗分子靶点的重要性。基于其在细胞生长和分化中的作用，我们评估了人类肝细胞癌中mTOR信号通路的激活情况，以及mTOR通路双重阻断的抗肿瘤效应。
利用来自351个人类样本（包括314例肝细胞癌和37例非肿瘤组织）的突变分析（直接测序）、DNA拷贝数变化（单核苷酸多态性阵列）、mRNA水平（实时定量聚合酶链反应和基因表达微阵列）以及蛋白质激活（免疫染色）的综合数据对mTOR通路进行了评估。在肝癌细胞系和肿瘤异种移植模型中评估了使用雷帕霉素类似物（依维莫司）和一种表皮生长因子受体/血管内皮生长因子受体抑制剂（AEE788）对mTOR信号通路进行双重阻断的效果。
在半数病例中存在异常的mTOR信号通路（磷酸化核糖体蛋白S6），与胰岛素样生长因子通路激活、表皮生长因子上调以及磷酸酶和张力蛋白同源物（PTEN）失调有关。PTEN和PI3KCA - B突变是罕见事件。RICTOR的染色体增益（25%的患者）以及磷酸化核糖体蛋白S6阳性染色与复发相关。RICTOR特异性小干扰RNA下调在体外降低了肿瘤细胞的活力。在体外和异种移植模型中用依维莫司阻断mTOR信号通路减缓了肿瘤生长并提高了生存率。在体内阻断表皮生长因子受体后这种效应增强。
mTOR信号通路在肝细胞癌的发病机制中起关键作用，有证据表明RICTOR在肿瘤发生中起作用。用依维莫司阻断mTOR在体内是有效的。这些发现为在肝细胞癌临床试验中靶向mTOR通路提供了理论依据。
The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. Based on its role in cell growth and differentiation, we evaluated mTOR signaling activation in human HCC, as well as the anti-tumoral effect of a dual-level blockade of the mTOR pathway. The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), mRNA levels (qRT-PCR and gene expression microarray), and protein activation (immunostaining) in 351 human samples, including HCC (n=314), and non-tumoral tissue (n=37). Effects of dual blockade of mTOR signaling using a rapamycin analog (everolimus) and an EGFR/VEGFR inhibitor (AEE788) were evaluated in liver cancer cell lines, and in a tumor xenograft model. Aberrant mTOR signaling (phosphorylated-RPS6) was present in half of the cases, associated with IGF pathway activation, EGF upregulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive pRPS6 staining correlated with recurrence. RICTOR-specific siRNA downregulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after EGFR blockade. MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in tumor oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting mTOR pathway in clinical trials in HCC.
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影响因子：
11.5
作者：
Sahin, F;Kannangai, R;Torbenson, M
通讯作者：
Torbenson, M
影响因子：
29.4
作者：
Llovet, Josep M.;Chen, Yingbei;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
影响因子：
6.2
作者：
Sieghart, Wolfgang;Fuereder, Thorsten;Wacheck, Volker
通讯作者：
Wacheck, Volker