Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications

Abstract

Human Endogenous Retroviruses (HERVs) are viral sequences integrated into the human genome, resulting from the infection of human germ-line cells by ancient exogenous retroviruses. Despite losing their replication and retrotransposition abilities, HERVs appear to have been co-opted in human physiological functions while their aberrant expression is linked to human disease. The role of HERVs in multiple malignancies has been demonstrated, however, the extent to which HERV activation and expression participate in the development of cancer is not yet fully comprehended. In this review article, we discuss the presumed role of HERVs in carcinogenesis and their promising diagnostic and prognostic implications. Additionally, we explore recent data on the HERVs in cancer therapeutics, either through the manipulation of their expression, to induce antitumor innate immunity responses or as cancer immunotherapy targets. Finally, more precise and higher resolution high-throughput sequencing approaches will further elucidate HERV participation in human physiological and pathological processes.

Keywords: HERV-K (HML-2); HERVs in oncogenesis; cancer; evolution; human endogenous retrovirus.

Figure 1

HERV life cycle. HERVS are viral sequences integrated into the human genome, resulting from multiple invasion events of ancient exogenous retroviruses, after their horizontal transmission and the occurrence of retroviral epidemics. Endogenization occurred after the infection of germ‐line cells and subsequent vertical transmission, and these elements either became extinct or reached fixation in the human genome, HERVs are vertically transmitted via Mendelian inheritance and are found scattered throughout the host's genome. HERVs, human endogenous retroviruses.

Figure 2

Oncogenic mechanisms related to Syncytin 1 expression: the examples of endometrial and hepatocellular carcinoma. (A) Upregulation of Syncytin‐1 mediated by the cAMP pathway leads to increased cellular fusion and thus increased invasiveness in endometrial carcinoma. (B) Syncytin‐1 leads to the development of malignant features in hepatocellular carcinoma cells through the activation of the MEK/ERK pathway and has been correlated to doxorubicin resistance. cAMP, cyclic adenosine monophosphate; ERK, extracellular‐signal regulated kinase; MEK, mitogen‐activated protein kinase. Created with BioRender.com.

Figure 3

HERV‐K related oncogenesis. (A) LTRs through their promoter and enhancer functions modulate the expression of host genes and thus participate in human carcinogenesis. (B) HERV‐K protein expression appears to exert oncogenic functions including the induction of the hallmarks of cancer and increased cellular oxidative stress, the activation of cancer‐related molecular pathways like the ERK, AKT, and Notch pathway, and the upregulation of β‐catenin. Furthermore, Np9 and Rec seem to bind to ZFPs (PLZF and TZFP) and prevent them from repressing the c‐myc proto‐oncogene expression. Finally, HERV‐K specific immunogenicity has been correlated to multiple malignancies. (C) Presence of HERV‐K noninfectious virions and viral‐like particles have been correlated to human malignancy, most strikingly in the case of teratocarcinoma. (D) Transactivation of HERVs induced by known onco‐virus and intra‐viral interactions between HERV‐K and onco‐viruses have also been linked to the development of the hallmarks of cancer in multiple virally mediated cancers. ERK, extracellular‐signal regulated kinase; HERV, human endogenous retrovirus; LTR, long terminal repeat; PLZF, promyelocytic leukemia zinc finger; TZFP, testicular zinc finger protein; ZFP, zinc finger protein. Created with BioRender.com.