Overexpression of eukaryotic elongation factor eEF2 in gastrointestinal cancers and its involvement in G2/M progression in the cell cycle
Overexpression of eukaryotic elongation factor eEF2 in gastrointestinal cancers and its involvement in G2/M progression in the cell cycle
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DOI：
10.3892/ijo_00000246
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发表时间：
2009-05-01
影响因子：
5.2
通讯作者：
Oji, Yusuke
中科院分区：
文献类型：
--
作者：
Nakamura, Junya;Aoyagi, Sayaka;Oji, Yusuke
高水平的蛋白质合成是癌细胞的特征之一。本研究的目的是显示真核细胞延伸因子2（eEF 2），这在多肽链延伸步骤中起着至关重要的作用，在胃肠道肿瘤的肿瘤发生的贡献。在本研究中，我们通过免疫组化证实eEF 2蛋白在92.9%（13/14）的胃癌和91.7%（22/24）的结直肠癌中过表达。在6例胃癌和6例结直肠癌中未发现eEF 2基因的任何外显子突变。通过eEF 2特异性短发夹RNA（shEF 2）敲低eEF 2抑制两种胃癌细胞系AZ-521和MKN 28以及一种结肠癌细胞系SW 620中的癌细胞生长。流式细胞仪分析表明，敲低eEF 2诱导G2/M期阻滞，并导致Akt和cdc 2（G2/M期调节因子）的失活和eEF 2激酶（eEF 2的负调节因子）的激活。相反，在AZ-521细胞中强制表达eEF 2通过促进细胞周期的G2/M进展、激活Akt和cdc 2以及失活eEF 2激酶而显著促进细胞生长。此外，在这些癌细胞中强制表达eEF 2增强了小鼠异种移植模型中的体内致瘤性。这些结果表明，eEF 2在胃肠道肿瘤中的过表达促进了G2/M进程，并增强了其细胞生长。体外和体内。这些结果还表明，翻译延伸和细胞周期机制之间的一种新的联系，这意味着该联系可能发挥重要作用，协调失调的翻译和细胞周期机制，促进胃肠道肿瘤的发展。
A high level protein synthesis is one of the characteristics of cancer cells. The aim of this study is to show the contribution of eukaryotic elongation factor 2 (eEF2), which plays an essential role in the polypeptide chain elongation step, in the tumorigenesis of gastrointestinal cancers. In the present study, we demonstrated by using immunohistochemistry that eEF2 protein was overexpressed in 92.9% (13 of 14) of gastric and 91.7% (22 of 24) of colorectal cancers. No mutations were found in any of the exons of the eEF2 gene in six gastric and six colorectal cancers. Knockdown of eEF2 by eEF2-specific short-hairpin RNA (shEF2) inhibited cancer cell growth in two gastric cancer cell lines, AZ-521 and MKN28, and one colon cancer cell line, SW620. Flow cytometric analysis showed that knockdown of eEF2 induced G2/M arrest and resulted in inactivation of Akt and cdc2 (a G2/M regulator) and activation of eEF2 kinase (a negative regulator of eEF2) in these cancer cells. Conversely, forced expression of eEF2 in AZ-521 cells significantly enhanced the cell growth through promotion of G2/M progression in cell cycle, activated Akt and cdc2, and inactivated eEF2 kinase. Furthermore, forced expression of eEF2 in these cancer cells enhanced in vivo tumorigenicity in a mouse xenograft model. These results showed that overexpressed eEF2 in gastrointestinal cancers promoted G2/M progression and enhanced their cell growth it? vitro and in vivo. These results also suggested a novel linkage between translational elongation and cell cycle mechanisms, implying that the linkage might play an important role to orchestrate the deregulated translation and cell cycle mechanisms for promotion of the development of gastrointestinal cancers.