Argonaute2 Promotes Tumor Metastasis by Way of Up-regulating Focal Adhesion Kinase Expression in Hepatocellular Carcinoma
Argonaute2 Promotes Tumor Metastasis by Way of Up-regulating Focal Adhesion Kinase Expression in Hepatocellular Carcinoma
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DOI：
10.1002/hep.26202
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发表时间：
2013-05-01
期刊：
影响因子：
13.5
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
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作者：
Cheng, Na;Li, Yandong;Han, Ze-Guang
肝细胞癌（HCC）是最常见的癌症之一，并表现出转移和浸润邻近和更远处组织的倾向。然而，导致肿瘤转移的机制仍不清楚。在这里，我们评估了 Argonaute2 (Ago2)（Ago 基因家族的成员）对 HCC 肿瘤发生和转移的影响，该基因在短干扰 RNA 介导的基因沉默中发挥作用。我们发现，与相应的邻近非肿瘤肝脏相比，Ago2 在 HCC 标本中经常上调。有趣的是，Ago2过表达可以促进体内HCC细胞的增殖、以锚定无关方式形成集落、迁移、致瘤和转移；相反，Ago2敲低可以限制体内HCC细胞的锚独立集落形成、迁移和肿瘤转移。然而，已知的与肿瘤转移相关的 microRNA 似乎不会因 HCC 细胞中 Ago2 的过度表达而失调；即使敲除负责 microRNA 生物合成的 Dicer，也没有消除 Ago2 在 HCC 细胞中的作用。值得注意的是，粘着斑激酶（FAK）是一种与肿瘤转移相关的众所周知的分子，由于 Ago2 过度表达而上调。染色质免疫沉淀实验表明Ago2可以与FAK启动子结合并触发其转录。此外，通过荧光原位杂交验证并显示了染色体 8q24（最常见的 DNA 扩增区域之一）上 Ago2 的 DNA 拷贝数增加。结论：我们的数据表明，基因组 DNA 扩增导致 Ago2 过表达，通过上调 FAK 转录促进 HCC 肿瘤发生和转移，从而为 HCC 进展和 Ago2 功能提供新的见解。 （肝病学 2013；57：1906-1918）
Hepatocellular carcinoma (HCC) is one of the most common cancers and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effect of Argonaute2 (Ago2), a member of the Ago gene family that plays a role in short interfering RNA-mediated gene silencing, on HCC tumorigenesis, and metastasis. We found that Ago2 was frequently up-regulated in HCC specimens compared to that in corresponding adjacent nontumor liver. Interestingly, Ago2 overexpression can promote proliferation, colony formation in an anchor-independent manner, migration, tumorigenicity, and metastasis of HCC cells in vivo; in contrast, Ago2 knockdown can restrict anchor-independent colony formation, migration, and tumor metastasis of HCC cells in vivo. However, known microRNAs related to tumor metastasis appeared not be deregulated with Ago2 overexpression in HCC cells; even the knockdown of Dicer, which is responsible for microRNA biosynthesis, did not abolish the actions of Ago2 in HCC cells. Significantly, focal adhesion kinase (FAK), a well-known molecule associated with tumor metastasis, was upregulated as a result of Ago2 overexpression. Chromatin immunoprecipitation assay showed that Ago2 can bind to the FAK promoter and then trigger its transcription. Moreover, an increased DNA copy number of Ago2 on chromosome 8q24, one of the most frequent DNA amplified regions, was validated and shown by way of fluorescence in situ hybridization. Conclusion: Our data demonstrate that Ago2 overexpression, as a result of genomic DNA amplification, promotes HCC tumorigenesis and metastasis by way of upregulation of FAK transcription, thereby providing new insight into HCC progression and Ago2 function. (HEPATOLOGY 2013;57:1906-1918)