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


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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 invasionin vitroby the down-regulation ofK-RAS, MMP11andPBX3, as well as tumour growth and metastasesin vivo, whereas inhibition of let-7c in low-metastatic HT29 cells increased cell motility and invasion by the enhanced gene expression ofK-RAS, MMP11andPBX3. Interestingly, the luciferase reporters' activities with the 3′-UTRs ofK-RAS, MMP11andPBX3were 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, bothin vitroandin vivo. Finally, the levels of let-7c were inversely correlated with those ofMMP11andPBX3, but not with those ofK-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 ofMMP11andPBX3at least. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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