Boregowda Rajeev K, Medina Daniel J, Markert Elke, Bryan Michael A, Chen Wenjin, Chen Suzie, Rabkin Anna, Vido Michael J, Gunderson Samuel I, Chekmareva Marina, Foran David J, Lasfar Ahmed, Goydos James S, Cohen-Solal Karine A
Division 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.
Cancer Research UK Beatson Institute, Glasgow, G61 1BD Scotland, UK.
Oncotarget. 2016 May 17;7(20):29689-707. doi: 10.18632/oncotarget.8822.
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.
基于受体酪氨酸激酶的自分泌环在很大程度上有助于激活黑色素瘤中的MAPK和PI3K/AKT信号通路。然而，产生这些自分泌环所涉及的分子机制仍大多未知。在本研究中，我们研究了转录因子RUNX2在黑色素瘤中调节受体酪氨酸激酶（RTK）表达的作用。我们已经证明，缺乏RUNX2的黑色素瘤细胞中三种受体酪氨酸激酶EGFR、IGF-1R和PDGFRβ的表达显著降低。此外，我们在黑色素瘤细胞和黑色素瘤患者样本中发现了RUNX2与另一种RTK——AXL的共表达。当RUNX2敲低导致RTK显著下调时，我们观察到磷酸化AKT2（S474）和磷酸化AKT（T308）水平降低。最后，我们发现在对BRAF V600E抑制剂PLX4720耐药的黑色素瘤细胞中，RUNX2表达显著上调，同时EGFR、IGF-1R和AXL也上调。综上所述，我们的结果强烈表明，RUNX2可能是基于RTK的自分泌环中的关键因子，也是黑色素瘤中涉及RTK上调的BRAF V600E抑制剂耐药的介导因子。
