Novel Metastasis-Related Gene CIM Functions in the Regulation of Multiple Cellular Stress-Response Pathways
Novel Metastasis-Related Gene CIM Functions in the Regulation of Multiple Cellular Stress-Response Pathways
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DOI：
10.1158/0008-5472.can-10-1055
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
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作者：
Yanagisawa, Kiyoshi;Konishi, Hiroyuki;Takahashi, Takashi
营养、pH和氧气不足所产生的肿瘤微环境的各种压力可导致代谢和增殖状态的改变，从而促进转移细胞的存活。在这种条件下激活的许多细胞应激反应通路包括低氧诱导因子(HIF)途径和未折叠蛋白反应(UPR)，UPR是对内质网(ER)应激的反应。在这项研究中，我们报告了一个新的癌症侵袭和转移相关基因(以下称为CIM，也称为ERLEC1)的发现，它影响这两个应激反应途径以促进转移。CIM是通过比较高转移的人肺癌细胞系和其弱转移的亲本克隆的基因表达谱来鉴定的。我们证明了CIM对于该系统中的转移特性是至关重要的。蛋白质组学方法结合生物信息学分析表明，CIM在控制对低氧和内质网应激的反应中具有多方面的作用。具体地说，CIM将OS-9与HIF-1α复合体和PHD2隔离，通过防止HIF-1α的降解来允许HIF-1α的积累。CIM在肺癌细胞中的异位表达增加了肺癌细胞对低氧的耐受性。CIM还通过与关键的内质网应激蛋白Bip相互作用来调节UPR，影响内质网应激条件下的细胞增殖。我们的发现揭示了如何通过涉及CIM的集成机制来激发对转移部位的多种细胞压力的耐受，该机制可以以促进转移细胞存活的方式协调这些反应。癌症资源；70(23)；9949-58。(C)2010年AACR。
Various stresses of the tumor microenvironment produced by insufficient nutrients, pH, and oxygen can contribute to the generation of altered metabolic and proliferative states that promote the survival of metastatic cells. Among many cellular stress-response pathways activated under such conditions are the hypoxia-inducible factor (HIF) pathway and the unfolded protein response (UPR), which is elicited as a response to endoplasmic reticulum (ER) stress. In this study, we report the identification of a novel cancer invasion and metastasis-related gene (hereafter referred to as CIM, also called ERLEC1), which influences both of these stress-response pathways to promote metastasis. CIM was identified by comparing the gene expression profile of a highly metastatic human lung cancer cell line with its weakly metastatic parental clone. We showed that CIM is critical for metastatic properties in this system. Proteomic approaches combined with bioinformatic analyses revealed that CIM has multifaceted roles in controlling the response to hypoxia and ER stress. Specifically, CIM sequestered OS-9 from the HIF-1 alpha complex and PHD2, permitting HIF-1 alpha accumulation by preventing its degradation. Ectopic expression of CIM in lung cancer cells increased their tolerance to hypoxia. CIM also modulated UPR through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress conditions. Our findings shed light on how tolerance to multiple cellular stresses at a metastatic site can be evoked by an integrated mechanism involving CIM, which can function to coordinate those responses in a manner that promotes metastatic cell survival. Cancer Res; 70(23); 9949-58. (C)2010 AACR.