CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis.
CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis.
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DOI：
10.1158/0008-5472.can-13-1617
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
You M
中科院分区：
文献类型：
--
作者：
James MA;Vikis HG;Tate E;Rymaszewski AL;You M
跨膜蛋白CLPTM 1 L在非小细胞肺癌（NSCLC）中过表达，它保护肿瘤细胞免受遗传毒性凋亡。在这里，我们表明，RNAi介导的CLPTM 1 L阻断抑制K-Ras诱导的肺肿瘤发生。CLPTM 1 L的表达在体外被H-RasV 12或K-RasV 12形态转化、非锚定依赖性生长和肺肿瘤细胞失巢凋亡的存活中是必需的。机制研究表明，CLPTM 1 L与PI 3 K相互作用，是Ras诱导的AKT磷酸化所必需的。此外，抗凋亡蛋白Bcl-xL受CLPTM 1 L调节，与AKT活化无关。AKT或Bcl-xL的组成性激活挽救了CLPTM 1 L耗尽细胞中的转化表型。CLPTM 1 L基因位于染色体5p15.33的癌症易感性位点内，该位点由全基因组关联研究定义。CLPTM 1 L位点的风险基因型与正常肺组织中CLPTM 1 L的高表达相关，表明CLPTM 1 L的顺式调节可能有助于肺癌风险。总之，我们的研究结果确立了CLPTM 1 L的促肿瘤作用，这对Ras驱动的肺癌至关重要，对治疗和化疗增敏具有潜在意义。
The transmembrane protein CLPTM1L is overexpressed in non-small cell lung cancer (NSCLC) where it protects tumor cells from genotoxic apoptosis. Here we show that RNAi-mediated blockade of CLPTM1L inhibits K-Ras-induced lung tumorigenesis. CLPTM1L expression was required in vitro for morphological transformation by H-RasV12 or K-RasV12, anchorage independent growth and survival of anoikis of lung tumor cells. Mechanistic investigations indicated that CLPTM1L interacts with PI3K and is essential for Ras-induced AKT phosphorylation. Further, that the anti-apoptotic protein Bcl-xL is regulated by CLPTM1L independently of AKT activation. Constitutive activation of AKT or Bcl-xL rescued the transformed phenotype in CLPTM1L-depleted cells. The CLPTM1L gene lies within a cancer susceptibility locus at chromosome 5p15.33 defined by genome-wide association studies. The risk genotype at the CLPTM1L locus was associated with high expression of CLPTM1L in normal lung tissue, suggesting that cis-regulation of CLPTM1L may contribute to lung cancer risk. Taken together, our results establish a pro-tumorigenic role for CLPTM1L that is critical for Ras-driven lung cancers, with potential implications for therapy and chemosensitization.