Systematic Identification of Endogenous Retroviral Protein-Coding Genes Expressed in Canine Oral Malignant Melanoma

Koichi Kitao,So Nakagawa,Yuki Matsumoto,Takayuki Miyazawa,Aoi Sumiyoshi,Takuya Mizuno

doi:10.3389/fviro.2021.785678

Abstract

Endogenous retroviruses (ERVs) are remnants of ancestral retroviruses that infected host germ cells in the past. Most ERVs are thought to be non-functional elements, but some ERVs retain open reading frames (ORFs) capable of expressing proteins. The proteins encoded by ERV-ORFs have potential roles in oncogenesis; however, studies on mammals other than humans and mice are limited. Here, we identified ERV-derived genes expressed in canine oral malignant melanoma (OMM). We identified 11 ERV-derived genes in our OMM samples. Differential expression gene analysis revealed that four ERV-derived genes (PEG10, LOC102155597, and two newly identified genes) were upregulated in OMM compared to healthy tissues. PEG10 is a conserved long terminal repeat (LTR)-type retrotransposon-derived gene among mammals and is involved in human cancers. LOC102155597 is a retroviral env gene conserved in Carnivora. This Env protein harbors an immunosuppressive domain, implying the potential adverse effects on the immune system. While the production of viral particles from ERVs has been reported in human and mouse melanoma, we found no ERV-derived genes having the potential to produce viral particles. These results provide insights into the different and conserved features of ERV-derived genes in mammalian melanoma.

Highlights

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections to germ cells and have accumulated in all mammalian genomes [1]
To identify ERV-derived genes from these sequence data, we constructed a pipeline to identify ERV-open reading frames (ORFs) expressed in canine melanoma (Figure 1A)
We obtained 106,209 transcripts from the 8 oral malignant melanoma (OMM) RNA-seq samples, and these transcripts were organized into 34,292 genes, of which 3,035 genes were not reported in the reference gene annotation (Figure 1B)

Summary

Introduction

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections to germ cells and have accumulated in all mammalian genomes [1]. Aberrant expression of ERVs has been reported to be associated with oncogenesis [2]. Human ERV-K (HERV-K) is actively expressed in human melanoma, and their protein expression, as well as particle formation, have been reported [3, 4]. Active expression of an ERV called MelARV has been reported in B16/BL6 melanoma cells [7, 8]. Knockdown of MelARV reduces the aggressiveness of B16 melanoma in transplanted mice [9]. They proposed a functional model in which Env protein of MelARV regulates regulatory T cells [9]. The association between melanoma and ERVs in mammals other than humans and mice remains unresolved

Methods

Results

Conclusion