Abstract
BackgroundThe nerve growth factor (NGF) receptor tyrosine-kinase TrkA is a well-known determinant of the melanocytic lineage, through modulation of the MAPK and AKT cascades. While TrkA gene is frequently rearranged in cancers, its involvement in malignant melanoma (MM) development is still unclear.MethodsWe analyzed a dataset of primary cutaneous MM (n = 31) by array comparative genomic hybridization (aCGH), to identify genomic amplifications associated with tumor progression. The analysis was validated by genomic quantitative PCR (qPCR) on an extended set of cases (n = 64) and the results were correlated with the clinical outcome. To investigate TrkA molecular pathways and cellular function, we generated inducible activation of the NGF-TrkA signaling in human MM cell lines.ResultsWe identified amplification of 1q23.1, where the TrkA locus resides, as a candidate hotspot implicated in the progression of MM. Across 40 amplicons detected, segmental amplification of 1q23.1 showed the strongest association with tumor thickness. By validation of the analysis, TrkA gene amplification emerged as a frequent event in primary melanomas (50 % of patients), and correlated with worse clinical outcome. However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA. These events were triggered via MAPK activity but not via AKT, and involved p21cip1 protein increase, compatibly with a mechanism of oncogene-induced growth arrest.ConclusionsTaken together, our findings point to TrkA as a candidate oncogene in MM and support a model in which the NGF-TrkA-MAPK pathway may mediate a trade-off between neoplastic transformation and adaptive anti-proliferative response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1791-y) contains supplementary material, which is available to authorized users.
Highlights
The nerve growth factor (NGF) receptor tyrosine-kinase tyrosine kinase protein (TrkA) is a well-known determinant of the melanocytic lineage, through modulation of the Mitogen-activated protein kinase (MAPK) and AKT cascades
To identify candidate oncogenes that participate in melanomagenesis, we retrospectively analyzed 31 primary MM samples, previously characterized for genomic profiles with array comparative genomic hybridization (aCGH) (GSE45354; ref. [15]), by exploring the association between genomic amplification and tumor thickness, a first-line clinical parameter of MM progression
In accordance with these previous histological data, the importance of NGF signaling in melanocyte biology [7], and its proved involvement in oncogenic pathways [4, 5], TrkA gene seems the most promising candidate for driving segmental amplification of the 1q23.1 region in MM, we cannot exclude the possibility that the other genes (INSRR, PEAR1, LRRC71, MIR765, ARHGEF11, ETV3L, ETV3) within the 1q23.1 minimal common amplification could participate in melanomagenesis
Summary
The nerve growth factor (NGF) receptor tyrosine-kinase TrkA is a well-known determinant of the melanocytic lineage, through modulation of the MAPK and AKT cascades. TrkA mediates the multiple effects of the nerve growth factor (NGF) signaling through receptor autophosphorylation and downstream induction of the mitogen-activated. Probably as a consequence of its predominant function in stimulating cell proliferation, deregulation of the TrkA pathway is common in cancers [5]. In this context, chromosomal translocation of region 1q23.1 is known as the major mechanism in oncogenic activation of TrkA, being observed in several cancer types [6]
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