Department of Surgery and Center for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong.
Int J Cancer. 2010 Aug 15;127(4):968-76. doi: 10.1002/ijc.25100.
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.
利用比较蛋白质组学和基因组学方法，作者鉴定出真核翻译起始因子 5A（eIF5A）作为一种在小鼠胚胎肝脏和人肝癌（HCC）细胞系中高度丰富的胎生分子。为了评估 eIF5A 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 病例中两种同工型（eIF5A1 和 eIF5A2）的表达模式。两种同工型在肿瘤中均有表达，临床相关的 eIF5A1 与更多数量的肿瘤结节相关，而 eIF5A2 与 HCC 中的肿瘤静脉浸润相关。在另一组 50 例 HCC 中，高水平的 eIF5A2，但不是 eIF5A1，与脱氧hypusine 合酶和脱氧hypusine 羟化酶的水平升高相关，这两种酶催化 eIF5A 蛋白的翻译后 hypusination。有趣的是，N1-鸟嘌呤-1,7-二氨基庚烷（GC7），它是 eIF5A hypusination 的第一步抑制剂，被证明可以显著抑制原代 HCC 细胞（HepG2 和 Hep3B）的增殖和侵袭。为了进一步证明与 eIF5A 相关的肿瘤发生作用，通过转染 Hep3B、H2-P 和 H2-M HCC 细胞，用针对 eIF5A2 的小干扰 RNA（siRNA）抑制高表达该同工型的细胞增殖，与 eIF5A2 的表达抑制相关。对于这些测定，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 eIF5A 在 HCC 肿瘤发生和转移中发挥重要作用，GC7 抑制剂或 RNAi 靶向 eIF5A hypusination 或 eIF5A2 可能为 HCC 患者提供新的治疗选择。
