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Review
. 2023 Mar 17;11(3):936.
doi: 10.3390/biomedicines11030936.

HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

Erik Stricker  1   2 , Erin C Peckham-Gregory  2 , Michael E Scheurer  1   2
Affiliations
Review

HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

Erik Stricker et al. Biomedicines. .

Abstract

Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.

Keywords: breast cancer; gastrointestinal cancer; human endogenous retrovirus; leukemia; liver cancer; lymphoma; prostate cancer; renal cancer; reproductive cancer; skin cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The role of HERVs in breast cancer. Evaluated treatments are marked in red. Abbreviations: Th1 = T helper cell 1, ER = estradiol receptor, PR = progesterone receptor, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, RT = reverse transcriptase, env = envelope. If not otherwise stated HERV-K = HML-2.
Figure 2
Figure 2
The effects of HERV-K (HML-2) Np9, Rec, and Env proteins on oncogenesis. LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, env = envelope, HERV-K = HML-2.
Figure 3
Figure 3
The role of HERVs in (a) lymphoma and (b) leukemia. Evaluated treatments are marked in red. Abbreviations: TF = transcription factor, HL = Hodgkin’s lymphoma, EBV = Epstein–Barr virus, CTCL = cutaneous T-cell lymphoma, DLBCL = diffuse large B-cell lymphoma, DNMT = DNA methyltransferases, HDAC = histone deacetylases, LTR = long terminal repeat, CML = chronic myelogenous leukemia, AML = acute myelogenous leukemia, B-CLL = B-cell chronic lymphocytic leukemia, vRNA = viral RNA, RT = reverse transcriptase, Env = envelope protein, TM = transmembrane domain, shNp9 = siRNA targeting np9, shFABP7 = siRNA targeting FABP7. If not otherwise stated HERV-K = HML-2.
Figure 3
Figure 3
The role of HERVs in (a) lymphoma and (b) leukemia. Evaluated treatments are marked in red. Abbreviations: TF = transcription factor, HL = Hodgkin’s lymphoma, EBV = Epstein–Barr virus, CTCL = cutaneous T-cell lymphoma, DLBCL = diffuse large B-cell lymphoma, DNMT = DNA methyltransferases, HDAC = histone deacetylases, LTR = long terminal repeat, CML = chronic myelogenous leukemia, AML = acute myelogenous leukemia, B-CLL = B-cell chronic lymphocytic leukemia, vRNA = viral RNA, RT = reverse transcriptase, Env = envelope protein, TM = transmembrane domain, shNp9 = siRNA targeting np9, shFABP7 = siRNA targeting FABP7. If not otherwise stated HERV-K = HML-2.
Figure 4
Figure 4
The role of HERVs in skin cancer. Evaluated treatments are marked in red. Abbreviations: LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, RT = reverse transcriptase, env = envelope, lncRNA = long non-coding RNA, shBANCR = siRNA targeting BANCR. If not otherwise stated HERV-K = HML-2.
Figure 5
Figure 5
The role of HERVs in genital cancers. Evaluated treatments are marked in red. Abbreviations: HDAC = histone deacetylases, Me = methylases, G9A = G9a methyltransferase, Pt = platinum treatment, HERV-K = HML-2.
Figure 6
Figure 6
The role of HERVs in colorectal cancer. Evaluated treatments are marked in red. Abbreviations: lncRNA = long non-coding RNA, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, env = envelope, HERV-K = HML-2.
Figure 7
Figure 7
The role of HERVs in liver and endocrine cancers. Evaluated treatments are marked in red. Abbreviations: HBV = hepatitis B virus, MAPK = MAP kinase, ab = antibody, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, RT = reverse transcriptase, env = envelope, HERV-K = HML-2.
Figure 8
Figure 8
The role of HERVs in nervous system tumors. Evaluated treatments are marked in red. Abbreviations: K+ = potassium, Ca2+ = calcium, ab = antibody, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, RT = reverse transcriptase, env = envelope, HERV-K = HML-2.
Figure 9
Figure 9
The role of HERVs in prostate cancer. Evaluated treatments are marked in red. Abbreviations: AR = androgen receptor, ab = antibody, lncRNA = long non-coding RNA, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, RT = reverse transcriptase, env = envelope, HERV-K = HML-2.
Figure 10
Figure 10
The role of HERVs in lung, head, and neck cancer. Evaluated treatments are marked in red. Abbreviations: LUAD = lung adenocarcinoma, LUSC = lung squamous cell carcinoma, GPCR = G-protein-coupled receptor, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, env = envelope. If not otherwise stated HERV-K = HML-2.
Figure 11
Figure 11
The role of HERVs in cancers of the urinary system. Evaluated treatments are marked in red. Abbreviations: CTL = cytotoxic T cell, UCC = urothelial carcinoma, RCC = renal cell carcinoma, piHERV = potentially immunogenic HERVs, LTR = long terminal repeat, gag = group antigen (capsid), pol = polymerase, env = envelope, HERV-K = HML-2.
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