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Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer

Authors

  • Hai-Bo Han,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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    • These authors contributed equally to this study.

  • Jin Gu,

    1. Department of Colorectal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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    • These authors contributed equally to this study.

  • Hui-Jing Zuo,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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    • These authors contributed equally to this study.

  • Zhi-Guo Chen,

    1. Department of Colorectal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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    • These authors contributed equally to this study.

  • Wei Zhao,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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  • Ming Li,

    1. Department of Colorectal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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  • Deng-Bo Ji,

    1. Department of Colorectal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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  • You-Yong Lu,

    1. Laboratory of Molecular Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China
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  • Zhi-Qian Zhang

    Corresponding author
    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, People's Republic of China
    • Department of Cell Biology, Peking University School of Oncology, 52 Fucheng Rd., Beijing 100142, China.
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  • No conflicts of interest were declared.

Abstract

Accumulating evidence shows that microRNAs, functioning as either oncogenes or tumour suppressors by negatively regulating downstream target genes that are actively involved in tumour initiation and progression, may be promising biomarkers and therapy targets. Data mining through a microRNA chip database indicated that let-7c may be associated with tumour metastasis. Here, we confirmed that down-regulation of let-7c in primary cancer tissues was significantly associated with metastases, advanced TNM stages and poor survival of colorectal cancer patients. Moreover, ectopic expression of let-7c in a highly metastatic Lovo cell line remarkably suppressed cell migration and invasion in vitro by the down-regulation of K-RAS, MMP11 and PBX3, as well as tumour growth and metastases in vivo, whereas inhibition of let-7c in low-metastatic HT29 cells increased cell motility and invasion by the enhanced gene expression of K-RAS, MMP11 and PBX3. Interestingly, the luciferase reporters' activities with the 3′-UTRs of K-RAS, MMP11 and PBX3 were inhibited significantly by let-7c. Importantly, rescue experiments involving the over-expression of these genes without their 3′-UTRs completely reversed the effects of let-7c on tumour metastasis, both in vitro and in vivo. Finally, the levels of let-7c were inversely correlated with those of MMP11 and PBX3, but not with those of K-RAS. Taken together, these results demonstrate that let-7c, apart from its tumour growth suppression role, also functions as a tumour metastasis suppressor in colorectal cancer by directly destabilizing the mRNAs of MMP11 and PBX3 at least. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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