MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1–Snail1 pathway in melanoma
Article first published online: 24 AUG 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 226, Issue 1, pages 61–72, January 2012
How to Cite
Liu, S., Kumar, S. M., Lu, H., Liu, A., Yang, R., Pushparajan, A., Guo, W. and Xu, X. (2012), MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1–Snail1 pathway in melanoma. J. Pathol., 226: 61–72. doi: 10.1002/path.2964
- Issue published online: 1 DEC 2011
- Article first published online: 24 AUG 2011
- Accepted manuscript online: 11 JUL 2011 03:43AM EST
- Manuscript Accepted: 27 JUN 2011
- Manuscript Revised: 13 JUN 2011
- Manuscript Received: 12 APR 2011
- National Institute of Health. Grant Numbers: CA-116103, CA-093372, AR-054593
MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate gene expression. Hsa-miR-9 has been shown to have opposite functions in different tumour types; however, the underlying mechanism is unclear. Here we show that hsa-miR-9 is down-regulated in metastatic melanomas compared to primary melanomas. Overexpression of miR-9 in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity with decreased F-actin polymerization and down-regulation of multiple GTPases involved in cytoskeleton remodelling. miR-9 overexpression induced significant down-regulation of Snail1 with a concomitant increase in E-cadherin expression. In contrast, knockdown of miR-9 increased Snail1 expression as well as melanoma cell proliferation and migration capacity. Mechanistically, miR-9 expression down-regulated NF-κB1 in melanoma and the effect was abolished by mutations in the putative miR-9 binding sites within the 3′-untranslated region (UTR) of NF-κB1. Anti-miR-9 miRNA inhibitor also increased the expression of NF-κB1. The effects of miR-9 on Snail1 expression and melanoma cell proliferation and migration were rescued by overexpression of NF-κB1 in these cells. Furthermore, miR-9 overexpression resulted in significantly decreased melanoma growth and metastasis in vivo. In summary, miR-9 inhibits melanoma proliferation and metastasis through down-regulation of the NF-κB1-Snail1 pathway. This study finds a new mechanism that miR-9 utilizes to decrease E-cadherin expression and inhibit melanoma progression. The results suggest that function of microRNAs is context and tumour type-specific. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.