Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors

Abstract

Germ cell tumors (GCTs) are among the most common malignancies in young men. We have previously documented that patients with GCT frequently produce serum antibodies directed against proteins encoded by human endogenous retrovirus (HERV) type K sequences. Transcripts originating from the env gene of HERV-K, including the rec-relative of human immunodeficiency virus rev, are highly expressed in GCTs. We report here that mice that inducibly express HERV-K rec show a disturbed germ cell development and may exhibit, by 19 months of age, changes reminiscent of carcinoma in situ, the predecessor lesion of classic seminoma in humans. This provides the first direct evidence that the expression of a human endogenous retroviral gene previously established as a marker in human germ cell tumors may contribute to organ-specific tumorigenesis in a transgenic mouse model.

Human endogenous retrovirus K (HERV-K) is expressed in villous and extravillous cytotrophoblast cells of the human placenta

“…The function of HERV-K during tumour development is still unclear. There is evidence that the accessory proteins Rec and Np9, encoded by different open reading frames in the env gene, might be involved in tumour development ( [Galli et al, 2005], [Boese et al, 2000] and [Armbruester et al, 2002]). On the other hand, the expression of HERV-K in tumours may be a secondary event based on activated transcription factors during tumourigenesis.…”

“…Different genes of HERV-K such as the gag gene, encoding for the core proteins, the pol gene encoding for the reverse transcriptase converting the genomic RNA into proviral DNA, and the env gene, encoding the envelope proteins involved in receptor recognition and membrane fusion, as well as the accessory proteins Rec and Np9 (Löwer et al, 1993), are expressed in germ cell tumours ( [Löwer et al, 1996] and [Götzinger et al, 1996]) and melanomas ( [Muster et al, 2003], [Büscher et al, 2005] and [Büscher et al, 2006]). There are several indications that Rec and Np9 may be involved in tumour induction ( [Boese et al, 2000], [Armbruester et al, 2002] and [Galli et al, 2005]). …”

The NP9 protein encoded by the human endogenous retrovirus HERV‐K(HML‐2) negatively regulates gene activation of the Epstein‐Barr virus nuclear antigen 2 (EBNA2)

“…13 Of these, the Rec protein encoded by HERV-K(HML-2) Type 2 has oncogenic properties. 14,15 NP9, a second env-encoded nuclear protein of 9kDa, is derived from HERV-K(HML-2) Type 1 env open reading frame due to a deletion in the env locus. 16 A schematic depiction of the HERV K101 Env transcripts can be seen in Armbruester et al, 2004.…”

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

“…In fact, Np9 and Rec have been shown to be highly expressed in transformed tissues (Np9), to cause carcinoma in situ in mice (Rec), and to be associ-ated with the Notch pathway and pathways affecting c-myc expression (Np9 and both, respectively) (13,15,16,(62)(63)(64)(65). Our laboratory has noted high expression levels of both proteins during HIV-1-associated lymphoma (unpublished observations).…”

“…This group of retroviruses is one of the most recent entrants into the human genome, with some proviruses having integrated either by reinfection or by intracellular transposition within the last 200,000 years, and they are the only HERVs with conserved and potentially functional open reading frames (ORFs) for all viral proteins (6,(9)(10)(11)(12). Thousands of HERV-K (HML-2) solo LTRs are found in the human genome, along with approximately 91 proviruses (4,9), some of which may encode the basic retroviral proteins and the accessory, putative oncogenes np9 and rec (4,(13)(14)(15)(16). The accessory genes np9 and rec are expressed by the two types of HERV-K (HML-2), type 1 and type 2 (9,17), respectively, which differ by only a 292-bp deletion in the env gene of type 1 viruses.…”