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Hatzl, S.* ; Geiger, O.* ; Kuepper, M.K.* ; Caraffini, V.* ; Seime, T.* ; Furlan, T.* ; Nussbaumer, E.* ; Wieser, R.* ; Pichler, M.* ; Scheideler, M. ; Nowek, K.* ; Lavrencic, M.* ; Quenhenberger, F.* ; Wölfler, A.* ; Troppmair, J.* ; Sill, H.* ; Zebisch, A.*

Increased expression of miR-23a mediates a loss of expression in the RAF kinase inhibitor protein RKIP.

Cancer Res. 76, 3644-3654 (2016)

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RAF kinase inhibitor protein (RKIP) is a seminal regulator of intracellular signaling and exhibits both anti-metastatic and anti-tumorigenic properties. Decreased expression of RKIP has been described in several human malignancies, including acute myeloid leukemia (AML). As the mechanisms leading to RKIP loss in AML are still unclear, we aimed to analyze the potential involvement of micro-RNAs (miRNAs) within this study. miRNA microarray and qPCR data of more than 400 AML patient specimens revealed correlation between decreased expression of RKIP and increased expression of miR-23a, a member of the miR-23a/27a/24-2 cluster. In functional experiments, overexpression of miR-23a decreased RKIP mRNA and protein expression, whereas miR-23a inhibition caused the opposite effect. By employing an RKIP 3'UTR luciferase reporter construct with and without mutation or deletion of the putative miR-23a binding site, we could show that RKIP modulation by miR-23a is mediated via direct binding to this region. Importantly, miR-23a overexpression induced a significant increase of proliferation in hematopoietic cells. Simultaneous transfection of an RKIP expression construct lacking the miR-23a binding sites reversed this phenotype, indicating that this effect is truly mediated via downregulation of RKIP. Finally, by analyzing more than 4300 primary patient specimens via database retrieval from The Cancer Genome Atlas (TCGA), we could highlight the importance of the miR-23a/RKIP axis in a broad range of human cancer entities. In conclusion, we have identified miR-23a as a negative regulator of RKIP expression in AML and have provided data that suggest the importance of our observation beyond this tumor entity.

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