Abstract
DUSP6/MKP-3, a specific inhibitor of MAPK1/ERK2, frequently loses its expression in primary pancreatic cancer tissues. This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression. By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA/STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA. An association of expression and promoter activity of AURKA with MAPK activity was verified. Knockdown of ETS2 resulted in a reduction of AURKA expression. These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2.
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Acknowledgements
We are grateful to Dr Barbara Lee Smith Pierce (an adjunct professor, University of Maryland University College) for editorial work in the preparation of this manuscript. This work was supported in part by Grant-in-Aid from Ministry of Education, Culture, Sports, Science and Technology of Japan, Public Trust Haraguchi Memorial Cancer Research Fund, Pancreas Research Foundation of Japan, Gonryo Medical Foundation, Foundation for promotion of Cancer Research in Japan, and the Program for promoting the establishment of Strategic Research Centers, Special Coordination Funds for promoting Science and Technology, Ministry of Education, Culture, Sports, Science and Technology (Japan).
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Furukawa, T., Kanai, N., Shiwaku, H. et al. AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer. Oncogene 25, 4831–4839 (2006). https://doi.org/10.1038/sj.onc.1209494
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DOI: https://doi.org/10.1038/sj.onc.1209494
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