A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion.

Cécile Lemaître,Jhen Tsang,Thierry Heidmann,Marie Dewannieux,Caroline Bireau,Susan R Ross

doi:10.1371/journal.ppat.1006451

Abstract

Endogenous retroviruses are cellular genes of retroviral origin captured by their host during the course of evolution and represent around 8% of the human genome. Although most are defective and transcriptionally silenced, some are still able to generate retroviral-like particles and proteins. Among these, the HERV-K(HML2) family is remarkable since its members have amplified relatively recently and many of them still have full length coding genes. Furthermore, they are induced in cancers, especially in melanoma, breast cancer and germ cell tumours, where viral particles, as well as the envelope protein (Env), can be detected. Here we show that HERV-K(HML2) Env per se has oncogenic properties. Its expression in a non-tumourigenic human breast epithelial cell line induces epithelial to mesenchymal transition (EMT), often associated with tumour aggressiveness and metastasis. In our model, this is typified by key modifications in a set of molecular markers, changes in cell morphology and enhanced cell motility. Remarkably, microarrays performed in 293T cells reveal that HERV-K(HML2) Env is a strong inducer of several transcription factors, namely ETV4, ETV5 and EGR1, which are downstream effectors of the MAPK ERK1/2 and are associated with cellular transformation. We demonstrate that HERV-K(HML2) Env effectively activates the ERK1/2 pathway in our experimental setting and that this activation depends on the Env cytoplasmic tail. In addition, this phenomenon is very specific, being absent with every other retroviral Env tested, except for Jaagsiekte Sheep Retrovirus (JSRV) Env, which is already known to have transforming properties in vivo. Though HERV-K Env is not directly transforming by itself, the newly discovered properties of this protein may contribute to oncogenesis.

Highlights

Retroviruses are responsible for a broad range of diseases in animals and humans, the most common of which is the development of cancers
We show that the HERV-K(HML2) envelope protein is able to activate a major cellular signalling pathway often involved in human cancers, and that its expression promotes a series of cellular changes that are characteristic of cancer development
The mechanisms by which they contribute to oncogenesis are diverse and include: (i) insertional mutagenesis, due to activation of cellular proto-oncogenes by inserted proviruses, (ii) immunosuppression, by an immunosuppressive domain conserved in most retroviral envelope proteins and (iii) direct oncogenic activity, with some retroviruses encoding proteins with transforming activities leading to tumour formation

Summary

Introduction

Retroviruses are responsible for a broad range of diseases in animals and humans, the most common of which is the development of cancers. Whilst most ERVs are defective and have degenerated over time, others have retained some or all of their open reading frames (ORFs) and can encode potentially pathogenic viral proteins [10,11,12,13]. These elements are normally suppressed in healthy tissues but expression has been reported in animal and human cancers [14,15,16,17]. In several breast cancer-derived cell lines, HERV-K expression was recently shown to be important for cell motility and growth, both in vitro and in vivo [25]

Methods

Results

Conclusion