These authors contributed equally to this study.
Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer†
Version of Record online: 5 DEC 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 226, Issue 3, pages 544–555, February 2012
How to Cite
Han, H.-B., Gu, J., Zuo, H.-J., Chen, Z.-G., Zhao, W., Li, M., Ji, D.-B., Lu, Y.-Y. and Zhang, Z.-Q. (2012), Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J. Pathol., 226: 544–555. doi: 10.1002/path.3014
No conflicts of interest were declared.
- Issue online: 16 JAN 2012
- Version of Record online: 5 DEC 2011
- Accepted manuscript online: 7 OCT 2011 08:31AM EST
- Manuscript Accepted: 23 SEP 2011
- Manuscript Revised: 2 SEP 2011
- Manuscript Received: 30 JUN 2011
- colorectal cancer;
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.