Abstract
Melanoma arises from neural crest‐derived melanocytes which reside mostly in the skin in an adult organism. Epithelial–mesenchymal transition (EMT) is a tumorigenic programme through which cells acquire mesenchymal, more pro‐oncogenic phenotype. The reversible phenotype switching is an event still not completely understood in melanoma. The EMT features and increased invasiveness are associated with lower levels of the pivotal lineage identity maintaining and melanoma‐specific transcription factor MITF (microphthalmia‐associated transcription factor), whereas increased proliferation is linked to higher MITF levels. However, the precise role of MITF in phenotype switching is still loosely characterized. To exclude the changes occurring upstream of MITF during MITF regulation in vivo, we employed a model whereby MITF expression was inducibly regulated by shRNA in melanoma cell lines. We found that the decrease in MITF caused only moderate attenuation of proliferation of the whole cell line population. Proliferation was decreased in five of 15 isolated clones, in three of them profoundly. Reduction in MITF levels alone did not generally produce EMT‐like characteristics. The stem cell marker levels also did not change appreciably, only a sharp increase in SOX2 accompanied MITF down‐regulation. Oppositely, the downstream differentiation markers and the MITF transcriptional targets melastatin and tyrosinase were profoundly decreased, as well as the downstream target livin. Surprisingly, after the MITF decline, invasiveness was not appreciably affected, independently of proliferation. The results suggest that low levels of MITF may still maintain relatively high proliferation and might reflect, rather than cause, the EMT‐like changes occurring in melanoma.
Highlights
Malignant melanoma is an aggressive tumour of neuroectodermal origin that has a dismal prognosis if it is not excised at an early stage
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
Based on these experiments with cell lines, we suggest slightly modified model concerning the role of MITF in proliferation and invasiveness of melanoma cells
Summary
Malignant melanoma is an aggressive tumour of neuroectodermal origin that has a dismal prognosis if it is not excised at an early stage. Melanoma cells are very early phenotypically diversified and undergo phenotype switching resembling the EMT, through which they acquire considerable microheterogeneity resulting in plasticity, capability of invasion and migration. These properties lead to metastasis and poor prognosis [4,5,6,7]. The expression of the downstream differentiation markers melastatin and tyrosinase and the antiapoptotic MITF target livin diminished after DOXdependent reduction in MITF protein level Based on these experiments with cell lines, we suggest slightly modified model concerning the role of MITF in proliferation and invasiveness of melanoma cells. The data further suggest that more complex events may occur during the phenotype switching in melanoma that might be a more non-uniform process than previously anticipated and may be a cause (rather than a result of) of the low-MITF levels in the invasive subpopulations
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