FLJ10540-elicited cell transformation is through the activation of PI3-kinase/AKT pathway
FLJ10540-elicited cell transformation is through the activation of PI3-kinase/AKT pathway
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DOI：
10.1038/sj.onc.1210207
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发表时间：
2007-06-21
期刊：
影响因子：
8
通讯作者：
Chou, C-K
中科院分区：
文献类型：
--
作者：
Chen, C-H;Lu, P-J;Chou, C-K
后基因组时代的一个重大挑战是如何优先处理在肝细胞癌微阵列分析中发现的差异表达和未表征的新基因。其中一类是细胞周期调节基因，它们只在高等生物中进化，而在低等真核细胞中没有进化。对这些基因的表征可能会揭示一些新的人类癌症特有的异常。鉴定出一个新的转录本，即FLJ10540。定量逆转录聚合酶链式反应和免疫组织化学检测结果显示，FLJ10540在肝细胞癌中高表达。FLJ10540高表达患者的生存率低于低表达患者。功能鉴定表明，FLJ10540表现出与癌基因相关的许多特征，包括锚定非依赖性生长、在低血清水平下促进细胞生长以及在裸鼠体内诱导肿瘤形成。FLJ10540诱导的细胞转化是通过激活磷脂酰肌醇3‘-激酶(PI3K)/AKT通路来实现的。此外，FLJ10540与PI3K形成复合体，并能激活PI3K活性，为FLJ10540介导的肿瘤发生提供了机制基础。综合使用生物信息学搜索和经验数据，我们已经确定了一个新的癌基因，FLJ10540，它只在高等生物中保守。这一发现增加了FLJ10540成为治疗肝癌的潜在新治疗靶点的可能性。这些发现可能有助于开发新的治疗策略，能够阻断癌细胞中的PI3K/AKT途径。
A significant challenge in the post-genomic era is how to prioritize differentially expressed and uncharacterized novel genes found in hepatocellular carcinoma (HCC) microarray profiling. One such category is cell cycle regulated genes that have only evolved in higher organisms but not in lower eukaryotic cells. Characterization of these genes may reveal some novel human cancer-specific abnormalities. A novel transcript, FLJ10540 was identified. FLJ10540 is overexpressed in HCC as examined by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The patients with higher FLJ10540 expression had a poor survival than those with lower FLJ10540 expression. Functional characterization indicates that FLJ10540 displays a number of characteristics associated with an oncogene, including anchorage-independent growth, enhanced cell growth at low serum levels and induction of tumorigenesis in nude mice. FLJ10540-elicited cell transformation is mediated by activation of the phosphatidylinositol 3'-kinase (PI3K)/AKT pathway. Moreover, FLJ10540 forms a complex with PI3K and can activate PI3K activity, which provides a mechanistic basis for FLJ10540-mediated oncogenesis. Together, using a combination of bioinformatics searches and empirical data, we have identified a novel oncogene, FLJ10540, which is conserved only in higher organisms. The finding raises the possibility that FLJ10540 is a potential new therapeutic target for HCC treatment. These findings may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in cancer cells.