Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma
Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma
复制标题
DOI：
10.1002/ijc.25100
复制
发表时间：
2010-08-15
影响因子：
6.4
通讯作者：
Luk, John M.
中科院分区：
文献类型：
--
作者：
Lee, Nikki P.;Tsang, Felice H.;Luk, John M.
利用比较蛋白质组学和基因组学方法，作者鉴定了真核翻译起始因子5A（eIF 5A）作为在小鼠胚胎肝和人肝细胞癌（HCC）细胞系中高度丰富的癌胚分子。为了评价eIF 5A在HCC中的致癌作用和预后意义，我们通过cDNA微阵列研究了258例HCC病例中eIF 5A 1和eIF 5A 2的表达模式。两种eIF 5A亚型均在肿瘤中表达，临床上eIF 5A 1与更多的肿瘤结节数量相关，eIF 5A 2与HCC中的肿瘤静脉浸润相关。在50例HCC的单独队列中，高水平的eIF 5A 2而不是eIF 5A 1与催化eIF 5A蛋白翻译后羟腐胺赖氨酸化的脱氧羟腐胺赖氨酸合酶和脱氧羟腐胺赖氨酸羟化酶水平升高相关。有趣的是，N1-鸟苷基-1，7-二氨基庚烷（GC 7），其是eIF 5A hypusination的第一步的抑制剂，显示出显著损害原代HCC细胞（HepG 2和Hep 3B）的细胞增殖和侵袭。为了进一步证明与eIF 5A相关的致瘤作用，通过使用针对eIF 5A 2的小干扰RNA（siRNA）抑制表达高水平该同种型的Hep 3B、H2-P和H2-M HCC细胞，将细胞增殖的急剧减少与eIF 5A 2的抑制相关。对于这些试验，通常在正常肝细胞系中观察到较轻的反应。因此，这些发现表明eIF 5A在HCC肿瘤发生和转移中起重要作用，并且通过GC 7抑制剂或RNA干扰（RNAi）靶向eIF 5A hypusination可能为HCC患者提供新的治疗选择。
Using comparative proteomic and genomic approaches, the authors identified eukaryotic translation initiation factor 5A (eIF5A) as an oncofetal molecule highly abundant in mouse embryonic livers and human hepatocellular carcinoma (HCC) cell lines. To evaluate the oncogenic role and prognostic significance of eIF5A in HCC, we investigate the expression patterns of the two isoforms (eIF5A1 and eIF5A2) in a cohort of 258 HCC cases by cDNA microarray. Both eIF5A isoforms were expressed in the tumors, and clinically correlated eIF5A1 with more numbers of tumor nodules and eIF5A2 with tumor venous infiltration in HCC. In a separate cohort of 50 HCCs, high level of eIF5A2, but not eIF5A1, was associated with elevated levels of deoxyhypusine synthase and deoxyhypusine hydroxylase that catalyze post-translational hypusination of eIF5A protein. Interestingly, N1-guanyl-1,7-diaminoheptane (GC7), which is an inhibitor for the first step of eIF5A hypusination, was shown to significantly impair the cell proliferation and invasion of primary HCC cells (HepG2 and Hep3B). To further demonstrate the tumorigenic role associated with eIF5A, a drastic reduction of cell proliferation was associated with suppression of eIF5A2 by transfecting Hep3B, H2-P and H2-M HCC cells expressing high level of this isoform using small interfering RNA (siRNA) against eIF5A2. For these assays, a milder response was usually observed in normal hepatocyte cell line. Therefore, these findings suggest that eIF5A plays an important role in HCC tumorigenesis and metastasis, and targeting eIF5A hypusination by GC7 inhibitor or eIF5A2 by RNA interference (RNAi) may offer new therapeutic alternatives to HCC patients.