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

PLoS Pathog. 2017 Jun 26;13(6):e1006451. doi: 10.1371/journal.ppat.1006451. eCollection 2017 Jun.

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.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Cell Transformation, Neoplastic / genetics
  • Endogenous Retroviruses / genetics*
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Products, env / genetics
  • Humans
  • Jaagsiekte sheep retrovirus
  • MAP Kinase Signaling System / genetics*
  • Neoplasm Invasiveness
  • Sheep / genetics

Substances

  • Gene Products, env

Grant support

This work was supported by grants from the Centre National de la Recherche Scientifique and Ligue Nationale contre le Cancer (TH, Equipe labellisée). CL was supported by a fellowship from Fondation pour la Recherche Médicale and JT by a post-doctoral fellowship from Ligue Nationale contre le Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.