Translational regulation of XIAP expression and cell survival during hypoxia in human cholangiocarcinoma
Translational regulation of XIAP expression and cell survival during hypoxia in human cholangiocarcinoma
复制标题
DOI：
10.1053/j.gastro.2004.09.002
复制
发表时间：
2004-12-01
期刊：
影响因子：
29.4
通讯作者：
Patel, T
中科院分区：
文献类型：
--
作者：
Marienfeld, C;Yamagiwa, Y;Patel, T
背景与目的：肿瘤细胞抵抗缺氧等不利环境条件的能力促进肿瘤进展。我们已经表明，翻译失调有助于恶性胆管细胞的转化细胞生长。基因表达的翻译调控有助于对缺氧等环境变化做出立即和快速的反应。因此，我们的目的是评估缺氧期间细胞存活所涉及的翻译机制，并鉴定参与细胞对缺氧反应的特定翻译调节蛋白。方法：评估人胆管癌细胞对缺氧反应的细胞活力和细胞凋亡。通过放线菌酮或雷帕霉素或通过靶向删除真核起始因子 (eIF)-4E（一种使用小干扰 RNA (siRNA) 的限速翻译起始因子）来解除翻译过程的调控。使用蛋白质抗体微阵列来筛选缺氧期间表达的 eIF-4E 依赖性蛋白质。使用 siRNA 可以降低 X 连锁细胞凋亡抑制剂 (XIAP) 的表达。结果：恶性胆管细胞对缺氧诱导的细胞凋亡具有抵抗力。此外，缺氧期间细胞的生存需要蛋白质翻译。 eIF-4E 在恶性胆管细胞中过度表达。与对照组相比，siRNA 降低 eIF-4E 表达可降低肿瘤细胞对缺氧的抵抗力，增加 caspase-3 的激活和凋亡，并降低细胞存活率。 XIAP 被鉴定为缺氧期间表达的翻译调节蛋白。通过 siRNA 调节 XIAP 表达可减少体外和体内缺氧期间的细胞死亡。结论：人胆管癌细胞对缺氧具有很强的抵抗力。 XIAP 等存活蛋白的翻译调节是缺氧期间介导胆管癌存活的机制。
Background & Aims: Tumor progression is promoted by the ability of tumor cells to resist adverse environmental conditions such as hypoxia. We have shown that translational dysregulation contributes to transformed cell growth in malignant cholangiocytes. Translational regulation of gene expression can contribute to an immediate and rapid response to environmental changes such as hypoxia. Thus, our aims were to assess translational mechanisms involved in cell survival during hypoxia and to identify specific translationally regulated proteins involved in the cellular response to hypoxia. Methods: Cell viability and apoptosis in response to hypoxia were assessed in human cholangiocarcinoma cells. Translational processes were deregulated by cycloheximide or rapamycin or by targeted deletion of eukaryotic initiation factor (eIF)-4E, a rate-limiting translational initiation factor using small interfering RNA (siRNA). A protein antibody microarray was used to screen for eIF-4E-dependent proteins expressed during hypoxia. Expression of the X-linked inhibitor of apoptosis (XIAP) was decreased using siRNA. Results: Malignant cholangiocytes are resistant to hypoxia-induced apoptosis. Furthermore, cell survival during hypoxia required protein translation. eIF-4E was over expressed in malignant cholangiocytes. Reduction in eIF-4E expression by siRNA decreased tumor cell resistance to hypoxia, increased caspase-3 activation and apoptosis, and decreased cell survival compared with controls. XIAP was identified as a translationally regulated protein expressed during hypoxia. Modulation of XIAP expression by siRNA decreases cell death during hypoxia in vitro and in vivo. Conclusions: Human cholangiocarcinoma cells are highly resistant to hypoxia. Translational regulation of survival proteins such as XIAP is a mechanism mediating cholangiocarcinoma survival during hypoxia.