Research Papers:
The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma
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Abstract
Rajeev K. Boregowda1, Daniel J. Medina1, Elke Markert2, Michael A. Bryan1, Wenjin Chen3,4, Suzie Chen5, Anna Rabkin5, Michael J. Vido6, Samuel I. Gunderson7, Marina Chekmareva4, David J. Foran3,4, Ahmed Lasfar8,9, James S. Goydos10, Karine A. Cohen-Solal11
1Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
2Cancer Research UK Beatson Institute, Glasgow, G61 1BD Scotland, UK
3Center for Biomedical Imaging & Informatics, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
4Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
5Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, New Brunswick, NJ 08903, USA
6Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
7Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA
8Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
9Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
10Division of Surgical Oncology, Department of Surgery, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901, USA
11Section of Surgical Oncology Research, Department of Surgery, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
Correspondence to:
Karine A. Cohen-Solal, email: [email protected]
Keywords: melanoma, transcription factor, RUNX2, receptor tyrosine kinase, resistance to targeted therapy
Received: November 16, 2015 Accepted: March 28, 2016 Published: April 18, 2016
ABSTRACT
Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.
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