Endogenous retroviruses

Abstract

The genomes of vertebrates contain sequences that are similar to present-day exogenous retroviruses. Such sequences, called endogenous retroviruses (ERVs), have resulted from ancestral germ line infections by exogenous retroviruses which have thereafter been transmitted in a Mendelian fashion. By analogy to exogenous tumorigenic retroviruses, ERVs have been implicated in the pathogenesis of cancer. Cumulative evidence from animal models indicates that ERVs may participate in the process of malignant transformation or promote tumor growth, e.g. through insertional mutagenesis or via counteracting tumor immunosurveillance. Here, we review the role of ERVs in tumorigenesis with focus on human ERVs (HERVs) in human cancer. Although available data suggest a potential role of HERVs in human cancers, in particular germ cell tumors, the contributions of HERVs to human tumorigenesis warrant further elucidation. (Part of a multi-author review).

Evolutionary diversification of DYX1C1 transcripts via an HERV-H LTR integration event

“…Additionally, HERV insertions can modify the expression of nearby genes by altering promoter activity, providing poly-A signals, or donating alternative splice sites. One interesting example, the HERV-K element, has fulllength intact ORFs, and their remnants and proteins have been detected in breast cancer (Frank et al, 2008;Golan et al, 2008;Wang-Johanning et al, 2008), and testis cancer (Goedert et al, 1999;Ruprecht et al, 2008). Our data adds to the mounting evidence of HERV-associated gene expression alteration by showing that an HERV-H LTR insertion affects the expression of the DYX1C1 gene by providing a poly-A signal.…”

Human endogenous retrovirus protein Rec interacts with the testicular zinc-finger protein and androgen receptor

“…The HERV-K (HML-2) protein Rec, a homologue of the regulatory Rev/Rex RNA transporters of exogenous HIV and HTLV, and produced by an alternative transcript from the env ORF, has been implicated in the development and/ or progression of cancer, primarily germ-cell cancer, in several studies over the past decade (reviewed by Ruprecht et al, 2008). For example, as a sequel to work that showed that a very high percentage of patients with germ-cell tumours produce antibodies directed against HERV-K (HML-2) proteins, investigation of the various HERV proteins revealed that Rec (but not Gag or Env) is able to transform immortal fibroblasts to allow tumour growth in nude mice (Boese et al, 2000).…”

“…The rec gene is an alternatively spliced transcript derived from the full-length env ORF of HERV-K (HML-2) subtype 2, and env expression itself has, for instance, been correlated with breast cancer (Wang-Johanning et al, 2003). The highly conserved transmembrane domain of Env proteins has been documented to act immunosuppressively in vitro and in vivo, and thereby to subvert tumour immune surveillance (reviewed by Ruprecht et al, 2008). Another factor of interest in this context is np9, a transcript spliced from the env ORF of the HERV-K (HML-2) subtype 1 sequence carrying a 292 bp deletion within the env gene.…”

“…This gene encodes syncytin-1, a surface protein expressed in the placenta that is crucial for the efficient fusion of trophoblast cells to syncytiotrophoblasts (Blond et al, 2000;Mallet et al, 2004). Apart from their roles in normal physiology, HERV proteins have also been implicated in disease, in particular in the development and progression of cancers (reviewed by Ruprecht et al, 2008). Not only are specific RNA transcripts from the various HERV families detected in many primary tumours and tumour cell lines, but patients with germ-cell tumours often harbour serum antibodies directed against proteins encoded by the HERV-K (HML-2) family, and the expression of HERV-K (HML-2) Rec (Fig.…”

An alternative approach to medical genetics based on modern evolutionary biology. Part 4: HERVs in cancer

“…54 An interesting possibility is the potential of HERV proteins to act as tumour recognition antigens, thus provoking an anti-tumour immune response that might be beneficial in immunological surveillance and defence against cancers. Conversely, Manganey and colleagues have confirmed, in a series of studies, that the expression of the env protein of both exogenous retroviruses and HERV-H on the surface of tumour cells allows them to evade immune rejection.…”