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Society of Surgical Oncology 64th Annual Cancer Symposium

2011; Springer Science+Business Media; Volume: 18; Issue: S1 Linguagem: Inglês

10.1245/s10434-011-1552-3

1534-4681

Serdar Uğraş, E. N. Jacobsen, C Angeles, Elliott Brill, Penelope DeCarolis, Roderic O'Connor, Aimeé M. Crago, Raya Khanin, Nicholas D. Socci, Chris Sander, Thomas Tuschl, Samuel Singer, William C. Dooley, Jong-Dae Bong, Theo J. M. Ruers, Cornelis J.A. Punt, Frits van Coevorden, Jean-Pierre E. N. Pierie, Inne H.M. Borel Rinkes, Jonathan Lederman, G.J. Poston, Wolf O. Bechstein, M.A. Lentz, M. Mauer, Ryaz Chagpar, Y. Xing, Y. Nancy You, Yan Ang, Barry W. Feig, George J. Chang, Janice N. Cormier, I. Langer, Barış Kocaoğlu, Ulrich Güller, Carsten T. Viehl, Guido Sauter, O. R. Koechli, Gilles Berclaz, Markus Zuber,

Multiple and Secondary Primary Cancers

Introduction: microRNA-143 (miR-143) is significantly down-regulated in dedifferentiated liposarcoma (DDLS) relative to adipose tissue, and re-expression of miR-143 inhibits DDLS cell growth.We sought to determine the mechanism of this growth inhibition.Methods: A lentivirus-based system was used to re-express miR-143 in DDLS cells.The negative control was a non-specific scramble (Scr) sequence.Proliferation was assessed by measuring DNA content, and apoptosis assessed by the percentage of cells showing immunohistochemical staining of caspase-3.Microarray analysis was carried out to identify genes and signaling pathways regulated by miR-143.Inhibition of polo-like kinase (PLK1) was carried out by treating DDLS with BI 2536 (10 nM), a specific inhibitor.Results: Re-expression of miR-143, relative to Scr, decreased proliferation in DDLS cells by 57±11% (mean ± standard deviation) and induced apoptosis by >20 fold.Re-expression of miR-143 also significantly altered the expression of 268 genes (p<0.05, t-test).A computational analysis (Net-Box) comparing these 268 genes to known pathways and protein-protein interactions identified one unexpectedly dense gene module (p=0.04) that included PLK1 and protein regulator of cytokinesis 1 (PRC1), binding partners mediating mitosis and cytokinesis.Both are predicted direct miR-143 targets.The effect of miR-143 re-expression on PLK1 and PRC1 expression was validated using quantitative PCR; PLK1 expression decreased by 42±1% and PRC1 expression by 51±1%.Immunoblotting demonstrated that PLK1 protein expression was also decreased.In DDLS cells relative to adipocyte controls, PLK1 and PRC1 were upregulated 66±7 and 43±4 fold, respectively.Treatment with the PLK1 inhibitor suppressed proliferation of DDLS cells by 49±8%.Conclusion: Functional analysis of microRNA-143 identified PLK1 and PRC1 as novel miR-143 targets in DDLS.PLK1 inhibition holds promise as a therapeutic for this disease.