Research Highlights

A. Pertsemlidis
Dr. A. Pertsemlidis

The DAB2 (disabled homolog 2) gene encodes a mitogen-responsive phosphoprotein that is downregulated in multiple cancer types, suggesting that it functions as a tumor suppressor. Its role in lung tumorigenesis is not fully characterized, and the molecular mechanism by which DAB2 is downregulated in lung cancer remains elusive. We hypothesized that loss of expression of DAB2 is driven by the binding of microRNAs to specific nucleotide sequences in the 3’ untranslated region (UTR) of the DAB2 gene. A systematic analysis revealed that miR-93, a microRNA that is highly abundant in lung cancer, functions as a potent repressor of DAB2 expression by directly targeting the DAB2 3'UTR. Using in vitro and in vivo experiments, we demonstrated that miR-93 overexpression has an important role in promoting lung cancer cell growth, and that its oncogenic function is primarily mediated by its downregulation of DAB2 expression. miRNA target prediction algorithms indicated several other miRNAs in addition to miR-93 that could potentially regulate DAB2 expression. To directly evaluate the potential clinical relevance of these miRNAs, we examined the correlation between their expression and that of DAB2 in lung tumor specimens. Only miR-93 expression was significantly negatively correlated with DAB2 expression. Further investigation indicated that high tumor levels of miR-93 and low levels of DAB2 are correlated with poor survival in lung cancer patients. These findings strongly support a critical role for the miR-93/DAB2 pathway in determining lung cancer progression.

In summary, our study defines a novel oncogenic pathway in lung cancer that is mediated by miR-93-directed downregulation of DAB2. The discovery highlighted here clearly warrants further investigation to ascertain whether therapeutic tools targeting this pathway can be developed.

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