Differential expression of transposable elements in the medaka melanoma model.

Frederik Helmprobst,Barbara Klotz,Manfred Schartl,Jean-Nicolas Volff,Magali Naville,Corentin Dechaud,Susanne Kneitz

doi:10.1371/journal.pone.0251713

Abstract

Malignant melanoma incidence is rising worldwide. Its treatment in an advanced state is difficult, and the prognosis of this severe disease is still very poor. One major source of these difficulties is the high rate of metastasis and increased genomic instability leading to a high mutation rate and the development of resistance against therapeutic approaches. Here we investigate as one source of genomic instability the contribution of activation of transposable elements (TEs) within the tumor. We used the well-established medaka melanoma model and RNA-sequencing to investigate the differential expression of TEs in wildtype and transgenic fish carrying melanoma. We constructed a medaka-specific TE sequence library and identified TE sequences that were specifically upregulated in tumors. Validation by qRT- PCR confirmed a specific upregulation of a LINE and an LTR element in malignant melanomas of transgenic fish.

Highlights

Worldwide incidence of melanoma has steadily increased over the last decades [1] and prognosis of this most aggressive form of skin cancer is still very poor due its high metastatic potential
BlastX of «unknown» repeats against an in-house fish transposable element protein library was used to rename matching “unknown” elements according to their hits [22]
For Olat_rnd-5_family-280#LINE/I we found at chr16:7446391–7450254 a sequence with one open reading frames (ORF) containing three characteristic LINE transposable elements (TEs) domains followed by a polyA signal

Summary

Introduction

Worldwide incidence of melanoma has steadily increased over the last decades [1] and prognosis of this most aggressive form of skin cancer is still very poor due its high metastatic potential. Genomic instability leads to mutations, including chromosome structure rearrangements, point mutations, and microsatellite instability and other smaller structure variations within the genetic code These mutations can result in bypassing intra- and extracellular control systems, giving cancerous cells a growth advantage and inducing further selection towards higher malignancy [3]. Due to the high abundance (~45%) of transposable elements (TEs) in the human genome [4], they can be one major source of genomic instability and can lead, when activated, to further mutational changes within the genome. These changes may contribute to the increasing resistance of some cells against drugs during melanoma treatment and lead to further progression of the disease [5].

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Methods

Results