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.
Highlights
The RUNX (Runt-related transcription factor) family is comprised of three closely related transcription factors, RUNX1, RUNX2 and RUNX3
We suggest that RUNX2 may be a driver of increased receptor-tyrosine kinase (RTK)-based autocrine signaling in melanoma and a key player in resistance to targeted therapies involving up regulation of different receptor tyrosine kinase (RTK)
We initially demonstrated the over-expression of transcriptionally active RUNX2 in melanoma cell lines and melanoma samples as compared with primary melanocytes and melanocytic nevi respectively
Summary
The RUNX (Runt-related transcription factor) family is comprised of three closely related transcription factors, RUNX1, RUNX2 and RUNX3. These genes are defined by a highly conserved 128 amino acid DNA binding/proteinprotein interaction domain called the Runt-homology domain [1]. RUNX2 regulates the expression of genes closely associated with tumor progression, invasion and metastasis [1, 6,7,8,9] and has proangiogenic effects [10,11,12,13]. We showed that decreased RUNX2 expression was associated with a reduction in the expression of FAK [14], implicated in cell migration [9, 15] and melanoma metastasis [16,17,18]
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