Advertisement

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

Authors

  • Na Cheng,

    1. Shanghai Institute of Digestive Surgery & Human Genome Center, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
    Search for more papers by this author
    • These authors contributed equally to this study.

  • Yandong Li,

    1. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
    Search for more papers by this author
    • These authors contributed equally to this study.

  • Ze-Guang Han

    Corresponding author
    1. Shanghai Institute of Digestive Surgery & Human Genome Center, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China
    • Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China
    Search for more papers by this author
    • fax: +86-21-50800402


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from Chinese National Key Program on Basic Research (2010CB529204 and 2010CB529206), China National Key Projects for Infectious Disease (2012ZX10002012-008 and 2013ZX10002010-006), and National Natural Science Foundation of China (81071722) and the Shanghai Postdoctoral sustentation Fund (11R21420500).

Abstract

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 up-regulated 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 up-regulation of FAK transcription, thereby providing new insight into HCC progression and Ago2 function. (HEPATOLOGY 2013)

Ancillary