Journal
ONCOGENE
Volume 30, Issue 25, Pages 2888-2899Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.13
Keywords
non-small cell lung cancer; breast cancer; colorectal cancer; Axl; microRNA
Funding
- Alfried Krupp von Bohlen und Halbach Foundation, Essen
- Hella-Buhler-Foundation, Heidelberg
- Dr Ingrid zu Solms Foundation, Frankfurt/Main
- Hector Foundation, Weinheim, Germany
- FRONTIER Excellence Initiative of the University of Heidelberg
- BMBF, Bonn, Germany
- Walter Schulz Foundation, Munich, Germany
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Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3'-UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3'-UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung-or liver-metastases in a chorion-allantoic-membrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n = 44), miR-34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histo-types, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells. Oncogene (2011) 30, 2888-2899; doi:10.1038/onc.2011.13; published online 14 February 2011
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