Learning from Embryogenesis-A Comparative Expression Analysis in Melanoblast Differentiation and Tumorigenesis Reveals miRNAs Driving Melanoma Development.

Lisa Linck-Paulus,Daniel Völler,Lisa Lämmerhirt,Rainer Spang,Anja Katrin Bosserhoff,Silke Kuphal,Katharina Meyer,Julia C Engelmann,Norbert Eichner,Gunter Meister

doi:10.3390/jcm10112259

Abstract

Malignant melanoma is one of the most dangerous tumor types due to its high metastasis rates and a steadily increasing incidence. During tumorigenesis, the molecular processes of embryonic development, exemplified by epithelial–mesenchymal transition (EMT), are often reactivated. For melanoma development, the exact molecular differences between melanoblasts, melanocytes, and melanoma cells are not completely understood. In this study, we aimed to identify microRNAs (miRNAs) that promote melanoma tumorigenesis and progression, based on an in vitro model of normal human epidermal melanocyte (NHEM) de-differentiation into melanoblast-like cells (MBrCs). Using miRNA-sequencing and differential expression analysis, we demonstrated in this study that a majority of miRNAs have an almost equal expression level in NHEMs and MBrCs but are significantly differentially regulated in primary tumor- and metastasis-derived melanoma cell lines. Further, a target gene analysis of strongly regulated but functionally unknown miRNAs yielded the implication of those miRNAs in many important cellular pathways driving malignancy. We hypothesize that many of the miRNAs discovered in our study are key drivers of melanoma development as they account for the tumorigenic potential that differentiates melanoma cells from proliferating or migrating embryonic cells.

Highlights

Malignant melanoma is an aggressively metastatic tumor with a high incidence that has been increasing for years [1]
The analysis provided 89 miRNAs that were significantly regulated in both, primary tumor and metastasis-derived melanoma cell lines, compared to melanoblast-related cells (MBrCs) and normal human epidermal melanocyte (NHEM)
An example is some members of the well-characterized let-7 miRNA-family, which we found as strongly downregulated in melanoma cells compared to MBrCs and NHEMs

Summary

Introduction

Malignant melanoma is an aggressively metastatic tumor with a high incidence that has been increasing for years [1]. Melanoma cells can build stem-cell-like subpopulations that have the ability to differentiate into several cell lineages such as neural, mesenchymal, and endothelial cells [6,7,8]. These characteristic features show that melanoma cells can re-activate the pathways of neural crest differentiation and melanoblast migration, and reflect the high plasticity of malignant melanoma cells Two aspects are of particular importance during melanoma development: Melanoblasts, the precursors of melanocytes derived from the neural crest, exhibit several mechanisms during embryogenesis usually known from tumor cells, e.g., they actively migrate, adapt to different cellular environments, and “invade” the epidermis [4,5].

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