An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer
An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer
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DOI：
10.1002/ijc.25419
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发表时间：
2011-03
影响因子：
6.4
通讯作者：
Di Wu;K. Matsushita;H. Matsubara;F. Nomura;T. Tomonaga
中科院分区：
文献类型：
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作者：
Di Wu;K. Matsushita;H. Matsubara;F. Nomura;T. Tomonaga
解除蛋白质合成的管制在细胞转化中起着关键作用。几种翻译起始因子（eIFs）与恶性转化有关；因此，如果选择性地杀死癌细胞而不损害健康细胞，抑制eIFs可能是一种潜在的癌症治疗方法。其中一个潜在的分子靶点是癌症特异性剪接变体。我们之前已经证明eIF4H的一个剪接变体（异构体1）在原发性人类结直肠癌中过表达。我们的研究旨在探讨eIF4H异构体1是否有助于致癌，并可能成为人类癌症治疗的有效分子靶点。我们发现它在永生化小鼠成纤维细胞NIH3T3细胞中的过表达在裸鼠体内产生肿瘤。相反，利用特异性siRNA抑制eIF4H亚型1的表达，在体外和体内可抑制结肠癌细胞和皮下植入肿瘤的增殖。引人注目的是，eIF4H亚型1特异性siRNA对永生化人成纤维细胞的生长没有影响。更有趣的是，eIF4H异构体1的异位表达大大增加了cyclin D1的水平。另一方面，通过shRNA介导的eIF4H亚型1的抑制，cyclin D1降低。此外，共转染eIF4H亚型1 siRNA和cyclin D1表达质粒能够逆转eIF4H亚型1敲低对生长的抑制作用。这些结果表明，eIF4H亚型1通过激活致癌信号在致癌过程中发挥重要作用，可能成为癌症治疗的一个有希望的分子靶点。
Deregulation of protein synthesis plays a critical role in cell transformation. Several translation initiation factors (eIFs) have been implicated in malignant transformation; thus, suppression of eIFs could be a potential cancer therapy if cancer cells are selectively killed without damaging healthy cells. One of the potential molecular targets is a cancer‐specific splicing variant. We have previously shown that one of the splicing variants of eIF4H (isoform 1) was overexpressed in primary human colorectal cancer. Our study aimed to explore whether eIF4H isoform 1 contributes to carcinogenesis and could be an efficient molecular target for human cancer therapy. We found that its overexpression in immortalized mouse fibroblasts, NIH3T3 cells, generated tumors in nude mice. Conversely, suppression of eIF4H isoform 1 expression using specific siRNA inhibited the proliferation of colon cancer cells in vitro and subcutaneously implanted tumor in vivo. Strikingly, eIF4H isoform 1 specific siRNA showed no effect on the growth of immortalized human fibroblasts. More interestingly, ectopic expression of eIF4H isoform 1 greatly increased the cyclin D1 level. On the other hand, cyclin D1 decreased by shRNA‐mediated suppression of eIF4H isoform 1. Moreover, cotransfection of eIF4H isoform 1 siRNA and cyclin D1 expression plasmid was able to reverse the growth suppression effect of eIF4H isoform 1 knockdown. These results suggest that eIF4H isoform 1 plays an important role in carcinogenesis through the activation of oncogenic signaling and could be a promising molecular target for cancer therapy.