Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?

Abstract

Harbored as relics of ancient germline infections, human endogenous retroviruses (HERVs) now constitute up to 8% of our genome. A proportion of this sequence has been co-opted for molecular and cellular processes, beneficial to human physiology, such as the fusogenic activity of the envelope protein, a vital component of placentogenesis. However, the discovery of high levels of HERV-K mRNA and protein and even virions in a wide array of cancers has revealed that HERV-K may be playing a more sinister role-a role as an etiological agent in cancer itself. Whether the presence of this retroviral material is simply an epiphenomenon, or an actual causative factor, is a hotly debated topic. This review will summarize the current state of knowledge regarding HERV-K and cancer and attempt to outline the potential mechanisms by which HERV-K could be involved in the onset and promotion of carcinogenesis.

Keywords: Env; Gag; HERV-K; HERV-K activation; Np9; Rec; breast cancer; carcinogenesis; human endogenous retrovirus; immunomodulation; melanoma; oncogenesis; prostate cancer.

Figure 1.

Structure of HERV-K provirus. The full length (gag) HML-2 transcript encodes the gag, pro and pol polyproteins. A singly spliced transcript encodes the env polyprotein, while a doubly spliced transcript encodes either the Rec or Np9 accessory proteins depending on the presence or absence of a 292-bp deletion at the pol/env boundary–a characteristic that defines a HML-2 provirus as either Type 1 (deleted) or Type 2 (intact). HML-2 also expresses a 1.5-kb transcript of unknown function known as the hel transcript.

Figure 2.

Proposed model of HERV-K (HML-2)-driven cancer progression. Global DNA hypomethylation during early-stage cancer leads to activation of otherwise silenced TEs, including HERVs. A humoral response to HERV-K gag has been observed in some cancers. Such a response to high levels of HERV-K protein expression may culminate in chronic inflammation. Conversely, it has been hypothesized that HERV-K LTRs are responsive to inflammatory transcription factors–a phenomenon that may explain the high levels of HERV-K mRNA and protein seen in some inflammatory diseases. HERV-K (HML-2) accessory proteins Rec and Np9 have been shown to lead to the derepression of the c-myc protooncogene, while Np9 has been shown to co-activate Akt, Notch and ERK pathways in leukemia. Rec has also been observed to lead to the derepression of the androgen receptor, which directly or undirectly causes a further increase in HERV-K transcription. Overall, the synergistic effects of chronic inflammation and dysregulated signaling/protooncogene activation caused by HERV-K protein expression may help to create a protumorigenic microenvironment culminating in further proliferation and metastasis. Finally, it is important to note that an active, infectious HML-2 provirus has not been isolated to date, but the existence of such a particle cannot be ruled out. It would potentially be oncogenic via mechanisms such as insertional mutagenesis.