MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a “Genetic Switch” Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma

Abstract

Melanoma is a very aggressive neoplasm with a propensity to undergo progression and invasion early in its evolution. The molecular pathways underpinning invasion in melanoma are now just beginning to be elucidated, but a clear understanding of the transition from non-invasive to invasive melanoma cells remains elusive. Microphthalmia-associated transcription factor (MITF), is thought to be a central player in melanoma biology, and it controls many aspects of the phenotypic expression of the melanocytic lineage. However, recently the paired box transcription factor PAX3 was shown to transcriptionally activate POU3F2/BRN2, leading to direct repression of MITF expression. Here we present a theory to explain melanoma phenotype switching and discuss the predictions that this theory makes. One prediction is that independent and opposing roles for MITF and PAX3 in melanoma would be expected, and we present empirical evidence supporting this: in melanoma tissues PAX3 expression occurs independently of MITF, and PAX3 does not play a key role in melanoma cell proliferation. Furthermore, we show that knockdown of PAX3 inhibits cell migration in a group of “lower MITF” melanoma cell lines, while knockdown of MITF promotes cell migration in a complementary “higher MITF” group of melanoma cell lines. Moreover, the morphological effects of knocking down PAX3 versus MITF in melanoma cells were found to differ. While these data support the notion of independent roles for MITF and PAX3, additional experiments are required to provide robust examination of the proposed genetic switch theory. Only upon clear delineation of the mechanisms associated with progression and invasion of melanoma cells will successful treatments for invasive melanoma be developed.

Growth of Circulating Tumor Cell-Derived Colonies from Peripheral Blood of Melanoma Patients: Preliminary Characterization of Colony Composition

“…The majority of samples did not stain with the usual pan-melanoma reactive mAb, but generally marked only with MITF [23]. This nuclear transcription factor is currently believed to be pivotal for melanoma pigment gene regulation [24], as well as regulating melanoma proliferation versus differentiation [25] [26]. This observation also is supported by a prior study by Koyanagi et al, who found that PCR-based detection of MITF in blood correlated with an adverse outlook in advanced melanoma patients [27].…”

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

“…14,16 Meanwhile, PAX3 seems to repress MITF expression through POU3F2 (see below) in some melanomas. 17,18 α-Melanocyte-stimulating hormone (α-MSH) increases pigmentation through increasing tyrosinase (Tyr) expression in mouse B16-F1 melanoma cells, 19 as well as numerous additional pigmentation related genes (see below). Based on the results that α-MSH activates the cAMP-CREB signaling pathway and MITF activates TYR transcription, Bertolotto et al 20 and Price et al 21 hypothesized and found that cAMP-CREB signaling activates MITF-M transcription in a cis-acting fashion.…”

Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

“…BCL2 family anti-apoptotic factor transcription has been associated with high levels of MITF [25,71]. Other evidence suggests that cells exhibiting low MITF expression have greater potential for invasion and that decreasing expression of MITF in vitro promotes greater melanoma invasion [75]. Recently, it was shown that MITF suppresses invasion by reducing intracellular GTP pools by inducing guanosine monophosphate reductase (GMPR); decreased GTP availability results in downregulation of RAC1, RHO-A, and RHO-C [76].…”