Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.
Gastroenterology. 2014 Jun;146(7):1701-13.e9. doi: 10.1053/j.gastro.2014.02.029. Epub 2014 Feb 21.
BACKGROUND & AIMS: Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC).
We used quantitative real-time polymerase chain reaction and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and nontumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy-number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and hypoxia-inducible factor-1α (HIF1α). We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines and growth of ESCC xenograft tumors in nude mice.
Levels of eIF5A2 messenger RNA and protein were increased in >40% of ESCC samples compared with matched nontumor tissues, along with levels of HIF1α and vascular endothelial growth factor. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P < .001) and tissue invasion (P = .037), and shorter survival times of patients (P < .001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, and eIF5A2 knockdown or HIFα inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and vascular endothelial growth factor, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin.
eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with up-regulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases metastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway.
实体瘤常发生缺氧，导致缺氧反应基因激活。我们研究了过表达缺氧反应基因 eIF5A2 对食管鳞状细胞癌（ESCC）的影响。
我们使用定量实时聚合酶链反应和免疫组织化学分析比较配对的 ESCC 样本和非肿瘤食管组织中 eIF5A2 的表达，荧光原位杂交检测基因拷贝数改变。荧光素酶报告和染色质免疫沉淀分析用于研究 eIF5A2 与缺氧诱导因子-1α（HIF1α）之间的相互作用。我们确定了 eIF5A2 在 ESCC 细胞系中的过表达和敲低的影响以及裸鼠中 ESCC 异种移植肿瘤的生长。
与匹配的非肿瘤组织相比，超过 40%的 ESCC 样本中 eIF5A2 信使 RNA 和蛋白水平升高，同时 HIF1α 和血管内皮生长因子水平也升高。EIF5A2 水平升高与 ESCC 淋巴结转移（P <.001）和组织侵袭（P =.037）显著相关，与患者生存时间较短（P <.001）显著相关。在过表达 eIF5A2 的 35.14%的 ESCC 样本中检测到 eIF5A2 扩增。缺氧使 ESCC 细胞系中 eIF5A2 的表达增加 4-8 倍；我们观察到 eIF5A2 和 HIF1α 之间的双向调节。瞬时转染 ESCC 细胞系表达 eIF5A2 增加了它们的迁移和侵袭能力以及上皮-间充质转化的标志物，而 eIF5A2 敲低或 HIFα 抑制则降低了这些标志物的表达。在小鼠中，表达 eIF5A2 的 ESCC 细胞系生成的异种移植肿瘤比仅表达载体（对照）的细胞系生成肿瘤更快；它们还表达更高水平的 HIF1α 和血管内皮生长因子，并形成更多的微血管。用干扰 RNA 敲低 ESCC 细胞中的 eIF5A2 可降低其在小鼠中的异种移植肿瘤生长，特别是当小鼠接受多西紫杉醇或顺铂治疗时。
eIF5A2 在 ESCC 中通过基因扩增或缺氧过表达，并与 HIF1α 上调、转移和患者生存时间缩短相关。eIF5A2 的表达增加通过 HIF1α 介导的信号通路增加 ESCC 的转移和血管生成。
Zotero 插件