Human endogenous retroviruses in cancer: Expression, regulation and function (Review)

Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al: Initial sequencing and analysis of the human genome. Nature. 409:860–921. 2001. View Article : Google Scholar

Bannert N and Kurth R: The evolutionary dynamics of human endogenous retroviral families. Annu Rev Genomics Hum Genet. 7:149–173. 2006. View Article : Google Scholar

Hohn O, Hanke K and Bannert N: HERV-K(HML-2), the best preserved family of HERVs: Endogenization, expression, and implications in health and disease. Front Oncol. 3:2462013. View Article : Google Scholar

Garcia-Montojo M, Doucet-O'Hare T, Henderson L and Nath A: Human endogenous retrovirus-K (HML-2): A comprehensive review. Crit Rev Microbiol. 44:715–738. 2018. View Article : Google Scholar

Henzy JE and Coffin JM: Betaretroviral envelope subunits are noncovalently associated and restricted to the mammalian class. J Virol. 87:1937–1946. 2013. View Article : Google Scholar

Schommer S, Sauter M, Kräusslich HG, Best B and Mueller-Lantzsch N: Characterization of the human endogenous retrovirus K proteinase. J Gen Virol. 77:375–379. 1996. View Article : Google Scholar

George M, Schwecke T, Beimforde N, Hohn O, Chudak C, Zimmermann A, Kurth R, Naumann D and Bannert N: Identification of the protease cleavage sites in a reconstituted Gag polyprotein of an HERV-K(HML-2) element. Retrovirology. 8:302011. View Article : Google Scholar

Kjellman C, Sjögren HO and Widegren B: HERV-F, a new group of human endogenous retrovirus sequences. J Gen Virol. 80:2383–2392. 1999. View Article : Google Scholar

Kremer D, Gruchot J, Weyers V, Oldemeier L, Göttle P, Healy L, Ho Jang J, Kang T, Xu Y, Volsko C, Dutta R, et al: pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci USA. 116:15216–15225. 2019. View Article : Google Scholar

Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K, et al: Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 7:307ra1532015. View Article : Google Scholar

Terry SN, Manganaro L, Cuesta-Dominguez A, Brinzevich D, Simon V and Mulder LCF: Expression of HERV-K108 envelope interferes with HIV-1 production. Virology. 509:52–59. 2017. View Article : Google Scholar

Monde K, Terasawa H, Nakano Y, Soheilian F, Nagashima K, Maeda Y and Ono A: Molecular mechanisms by which HERV-K Gag interferes with HIV-1 Gag assembly and particle infectivity. Retrovirology. 14:272017. View Article : Google Scholar

Huang WJ, Liu ZC, Wei W, Wang GH, Wu JG and Zhu F: Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia. Schizophr Res. 83:193–199. 2006. View Article : Google Scholar

Yao Y, Schröder J, Nellåker C, Bottmer C, Bachmann S, Yolken RH and Karlsson H: Elevated levels of human endogenous retrovirus-W transcripts in blood cells from patients with first episode schizophrenia. Genes Brain Behav. 7:103–112. 2008.

Vargas A, Toufaily C, LeBellego F, Rassart E, Lafond J and Barbeau B: Reduced expression of both syncytin 1 and syncytin 2 correlates with severity of preeclampsia. Reprod Sci. 18:1085–1091. 2011. View Article : Google Scholar

Levet S, Charvet B, Bertin A, Deschaumes A, Perron H and Hober D: Human endogenous retroviruses and type 1 diabetes. Curr Diab Rep. 19:1412019. View Article : Google Scholar

Nogueira MA, Gavioli CF, Pereira NZ, de Carvalho GC, Domingues R, Aoki V and Sato MN: Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus. Arch Dermatol Res. 307:259–264. 2015. View Article : Google Scholar

Ariza ME and Williams MV: A human endogenous retrovirus K dUTPase triggers a TH1, TH17 cytokine response: Does it have a role in psoriasis? J Invest Dermatol. 131:2419–2427. 2011. View Article : Google Scholar

Fali T, Le Dantec C, Thabet Y, Jousse S, Hanrotel C, Youinou P, Brooks WH, Perl A and Renaudineau Y: DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus. Autoimmunity. 47:265–271. 2014. View Article : Google Scholar

Reynier F, Verjat T, Turrel F, Imbert PE, Marotte H, Mougin B and Miossec P: Increase in human endogenous retrovirus HERV-K (HML-2) viral load in active rheumatoid arthritis. Scand J Immunol. 70:295–299. 2009. View Article : Google Scholar

Johanning GL, Malouf GG, Zheng X, Esteva FJ, Weinstein JN, Wang-Johanning F and Su X: Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype. Sci Rep. 7:419602017. View Article : Google Scholar

Ma W, Hong Z, Liu H, Chen X, Ding L, Liu Z, Zhou F and Yuan Y: Human Endogenous retroviruses-K (HML-2) expression is correlated with prognosis and progress of hepatocellular carcinoma. Biomed Res Int. 2016:82016422016. View Article : Google Scholar

Li M, Radvanyi L, Yin B, Rycaj K, Li J, Chivukula R, Lin K, Lu Y, Shen J, Chang DZ, et al: Downregulation of human endogenous retrovirus type K (HERV-K) Viral env RNA in pancreatic cancer cells decreases cell proliferation and tumor growth. Clin Cancer Res. 23:5892–5911. 2017. View Article : Google Scholar

Chen T, Meng Z, Gan Y, Wang X, Xu F, Gu Y, Xu X, Tang J, Zhou H, Zhang X, et al: The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia. 27:1469–1478. 2013. View Article : Google Scholar

Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, Richaud A, Ducos B and Heidmann T: Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA. 104:20534–20539. 2007. View Article : Google Scholar

Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, et al: Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight. 3:e1215222018. View Article : Google Scholar

Tavakolian S, Goudarzi H and Faghihloo E: Evaluating the expression level of HERV-K env, np9, rec and gag in breast tissue. Infect Agent Cancer. 14:422019. View Article : Google Scholar

Ibba G, Piu C, Uleri E, Serra C and Dolei A: Disruption by SaCas9 endonuclease of HERV-Kenv, a retroviral gene with oncogenic and neuropathogenic potential, inhibits molecules involved in cancer and amyotrophic lateral sclerosis. Viruses. 10:4122018. View Article : Google Scholar

Galli UM, Sauter M, Lecher B, Maurer S, Herbst H, Roemer K and Mueller-Lantzsch N: Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors. Oncogene. 24:3223–3228. 2005. View Article : Google Scholar

Kreimer U, Schulz WA, Koch A, Niegisch G and Goering W: HERV-K and LINE-1 DNA methylation and reexpression in urothelial carcinoma. Front Oncol. 3:2552013. View Article : Google Scholar

Rycaj K, Plummer JB, Yin B, Li M, Garza J, Radvanyi L, Ramondetta LM, Lin K, Johanning GL, Tang DG and Wang-Johanning F: Cytotoxicity of human endogenous retrovirus K-specific T cells toward autologous ovarian cancer cells. Clin Cancer Res. 21:471–483. 2015. View Article : Google Scholar

Zare M, Mostafaei S, Ahmadi A, Azimzadeh Jamalkandi S, Abedini A, Esfahani-Monfared Z, Dorostkar R and Saadati M: Human endogenous retrovirus env genes: Potential blood biomarkers in lung cancer. Microb Pathog. 115:189–193. 2018. View Article : Google Scholar

Bergallo M, Montanari P, Mareschi K, Merlino C, Berger M, Bini I, Daprà V, Galliano I and Fagioli F: Expression of the pol gene of human endogenous retroviruses HERV-K and -W in leukemia patients. Arch Virol. 162:3639–3644. 2017. View Article : Google Scholar

Barth M, Gröger V, Cynis H and Staege MS: Identification of human endogenous retrovirus transcripts in Hodgkin Lymphoma cells. Mol Biol Rep. 46:1885–1893. 2019. View Article : Google Scholar

Aagaard L, Bjerregaard B, Kjeldbjerg AL, Pedersen FS, Larsson LI and Rossi JJ: Silencing of endogenous envelope genes in human choriocarcinoma cells shows that envPb1 is involved in heterotypic cell fusions. J Gen Virol. 93:1696–1699. 2012. View Article : Google Scholar

Liang Q, Xu Z, Xu R, Wu L and Zheng S: Expression patterns of non-coding spliced transcripts from human endogenous retrovirus HERV-H elements in colon cancer. PLoS One. 7:e299502012. View Article : Google Scholar

Giebler M, Staege MS, Blauschmidt S, Ohm LI, Kraus M, Würl P, Taubert H and Greither T: Elevated HERV-K expression in soft tissue sarcoma is associated with worsened relapse-free survival. Front Microbiol. 9:2112018. View Article : Google Scholar

Dai L, Del Valle L, Miley W, Whitby D, Ochoa AC, Flemington EK and Qin Z: Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi's sarcoma development. Oncogene. 37:4534–4545. 2018. View Article : Google Scholar

Montesion M, Bhardwaj N, Williams ZH, Kuperwasser C and Coffin JM: Mechanisms of HERV-K (HML-2) transcription during human mammary epithelial cell transformation. J Virol. 92:e01258–17. 2018.

Zhou F, Li M, Wei Y, Lin K, Lu Y, Shen J, Johanning GL and Wang-Johanning F: Activation of HERV-K Env protein is essential for tumorigenesis and metastasis of breast cancer cells. Oncotarget. 7:84093–84117. 2016. View Article : Google Scholar

Chan SM, Sapir T, Park SS, Rual JF, Contreras-Galindo R, Reiner O and Markovitz DM: The HERV-K accessory protein Np9 controls viability and migration of teratocarcinoma cells. PLoS One. 14:e02129702019. View Article : Google Scholar

van de Lagemaat LN, Medstrand P and Mager DL: Multiple effects govern endogenous retrovirus survival patterns in human gene introns. Genome Biol. 7:R862006. View Article : Google Scholar

Lee Y and Rio DC: Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem. 84:291–323. 2015. View Article : Google Scholar

Leib-Mösch C, Haltmeier M, Werner T, Geigl EM, Brack-Werner R, Francke U, Erfle V and Hehlmann R: Genomic distribution and transcription of solitary HERV-K LTRs. Genomics. 18:261–269. 1993. View Article : Google Scholar

Ng KW, Attig J, Young GR, Ottina E, Papamichos SI, Kotsianidis I and Kassiotis G: Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist. Elife. 8:e502562019. View Article : Google Scholar

Hassounah NB, Malladi VS, Huang Y, Freeman SS, Beauchamp EM, Koyama S, Souders N, Martin S, Dranoff G, Wong KK, et al: Identification and characterization of an alternative cancer-derived PD-L1 splice variant. Cancer Immunol Immunother. 68:407–420. 2019. View Article : Google Scholar

Bassani-Sternberg M, Bräunlein E, Klar R, Engleitner T, Sinitcyn P, Audehm S, Straub M, Weber J, Slotta-Huspenina J, Specht K, et al: Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat Commun. 7:134042016. View Article : Google Scholar

Attig J, Young GR, Hosie L, Perkins D, Encheva-Yokoya V, Stoye JP, Snijders AP, Ternette N and Kassiotis G: LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly. Genome Res. 29:1578–1590. 2019. View Article : Google Scholar

Laumont CM, Daouda T, Laverdure JP, Bonneil É, Caron-Lizotte O, Hardy MP, Granados DP, Durette C, Lemieux S, Thibault P and Perreault C: Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames. Nat Commun. 7:102382016. View Article : Google Scholar

Zhu Y, Orre LM, Johansson HJ, Huss M, Boekel J, Vesterlund M, Fernandez-Woodbridge A, Branca RMM and Lehtiö J: Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow. Nat Commun. 9:9032018. View Article : Google Scholar

Montesion M, Williams ZH, Subramanian RP, Kuperwasser C and Coffin JM: Promoter expression of HERV-K (HML-2) provirus-derived sequences is related to LTR sequence variation and polymorphic transcription factor binding sites. Retrovirology. 15:572018. View Article : Google Scholar

Knossl M, Lower R and Lower J: Expression of the human endogenous retrovirus HTDV/HERV-K is enhanced by cellular transcription factor YY1. J Virol. 73:1254–1261. 1999. View Article : Google Scholar

Ohtani H, Liu M, Zhou W, Liang G and Jones PA: Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. Genome Res. 28:1147–1157. 2018. View Article : Google Scholar

Gonzalez-Hernandez MJ, Cavalcoli JD, Sartor MA, Contreras-Galindo R, Meng F, Dai M, Dube D, Saha AK, Gitlin SD, Omenn GS, et al: Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 Tat protein. J Virol. 88:8924–8935. 2014. View Article : Google Scholar

Conti A, Rota F, Ragni E, Favero C, Motta V, Lazzari L, Bollati V, Fustinoni S and Dieci G: Hydroquinone induces DNA hypomethylation-independent overexpression of retroelements in human leukemia and hematopoietic stem cells. Biochem Biophys Res Commun. 474:691–695. 2016. View Article : Google Scholar

Subramanian RP, Wildschutte JH, Russo C and Coffin JM: Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology. 8:902011. View Article : Google Scholar

Liang Q, Ding J, Xu R, Xu Z and Zheng S: Identification of a novel human endogenous retrovirus and promoter activity of its 5′ U3. Biochem Biophys Res Commun. 382:468–472. 2009. View Article : Google Scholar

Fuchs NV, Kraft M, Tondera C, Hanschmann KM, Löwer J and Löwer R: Expression of the human endogenous retrovirus (HERV) group HML-2/HERV-K does not depend on canonical promoter elements but is regulated by transcription factors Sp1 and Sp3. J Virol. 85:3436–3448. 2011. View Article : Google Scholar

Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S and Zhu F: Mutations in 3′-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb. Oncogene. 33:3947–3958. 2014. View Article : Google Scholar

Katoh I, Mírová A, Kurata S, Murakami Y, Horikawa K, Nakakuki N, Sakai T, Hashimoto K, Maruyama A, Yonaga T, et al: Activation of the long terminal repeat of human endogenous retrovirus K by melanoma-specific transcription factor MITF-M. Neoplasia. 13:1081–1092. 2011. View Article : Google Scholar

Stacey KJ and Sagulenko V: A clear link between endogenous retroviral LTR activity and Hodgkin's lymphoma. Cell Res. 20:869–871. 2010. View Article : Google Scholar

Kriaucionis S and Tahiliani M: Expanding the epigenetic landscape: Novel modifications of cytosine in genomic DNA. Cold Spring Harb Perspect Biol. 6:a0186302014. View Article : Google Scholar

Brookes E and Shi Y: Diverse epigenetic mechanisms of human disease. Annu Rev Genet. 48:237–268. 2014. View Article : Google Scholar

Lavie L, Kitova M, Maldener E, Meese E and Mayer J: CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J Virol. 79:876–883. 2005. View Article : Google Scholar

Florl AR, Löwer R, Schmitz-Dräger BJ and Schulz WA: DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas. Br J Cancer. 80:1312–1321. 1999. View Article : Google Scholar

Menendez L, Benigno BB and McDonald JF: L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas. Mol Cancer. 3:122004. View Article : Google Scholar

Stengel S, Fiebig U, Kurth R and Denner J: Regulation of human endogenous retrovirus-K expression in melanomas by CpG methylation. Genes Chromosomes Cancer. 49:401–411. 2010. View Article : Google Scholar

Strissel PL, Ruebner M, Thiel F, Wachter D, Ekici AB, Wolf F, Thieme F, Ruprecht K, Beckmann MW and Strick R: Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets. Oncotarget. 3:1204–1219. 2012. View Article : Google Scholar

Hu L, Uzhameckis D, Hedborg F and Blomberg J: Dynamic and selective HERV RNA expression in neuroblastoma cells subjected to variation in oxygen tension and demethylation. APMIS. 124:140–149. 2016. View Article : Google Scholar

Bannister AJ and Kouzarides T: Regulation of chromatin by histone modifications. Cell Res. 21:381–395. 2011. View Article : Google Scholar

Krönung SK, Beyer U, Chiaramonte ML, Dolfini D, Mantovani R and Dobbelstein M: LTR12 promoter activation in a broad range of human tumor cells by HDAC inhibition. Oncotarget. 7:33484–33497. 2016. View Article : Google Scholar

Rajagopalan D, Tirado-Magallanes R, Bhatia SS, Teo WS, Sian S, Hora S, Lee KK, Zhang Y, Jadhav SP, Wu Y, et al: TIP60 represses activation of endogenous retroviral elements. Nucleic Acids Res. 46:9456–9470. 2018. View Article : Google Scholar

Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, Li Y, Chen H, Yang H, Hsu PH, et al: LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 174:549–563.e19. 2018. View Article : Google Scholar

Liu M, Thomas SL, DeWitt AK, Zhou W, Madaj ZB, Ohtani H, Baylin SB, Liang G and Jones PA: Dual inhibition of DNA and histone methyltransferases increases viral mimicry in ovarian cancer cells. Cancer Res. 78:5754–5766. 2018.

Audergon PN, Catania S, Kagansky A, Tong P, Shukla M, Pidoux AL and Allshire RC: Epigenetics. Restricted epigenetic inheritance of H3K9 methylation. Science. 348:132–135. 2015. View Article : Google Scholar

Matsui T, Leung D, Miyashita H, Maksakova IA, Miyachi H, Kimura H, Tachibana M, Lorincz MC and Shinkai Y: Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature. 464:927–931. 2010. View Article : Google Scholar

Sharma S, Gerke DS, Han HF, Jeong S, Stallcup MR, Jones PA and Liang G: Lysine methyltransferase G9a is not required for DNMT3A/3B anchoring to methylated nucleosomes and maintenance of DNA methylation in somatic cells. Epigenetics Chromatin. 5:32012. View Article : Google Scholar

Adoue V, Binet B, Malbec A, Fourquet J, Romagnoli P, van Meerwijk JPM, Amigorena S and Joffre OP: The histone methyltransferase SETDB1 controls T helper cell lineage integrity by repressing endogenous retroviruses. Immunity. 50:629–644.e8. 2019. View Article : Google Scholar

Imbeault M, Helleboid P-Y and Trono D: KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature. 543:550–554. 2017. View Article : Google Scholar

Thomas JH and Schneider S: Coevolution of retroelements and tandem zinc finger genes. Genome Res. 21:1800–1812. 2011. View Article : Google Scholar

Voon HPJ and Gibbons RJ: Maintaining memory of silencing at imprinted differentially methylated regions. Cell Mol Life Sci. 73:1871–1879. 2016. View Article : Google Scholar

Toufaily C, Landry S, Leib-Mosch C, Rassart E and Barbeau B: Activation of LTRs from different human endogenous retrovirus (HERV) families by the HTLV-1 tax protein and T-cell activators. Viruses. 3:2146–2159. 2011. View Article : Google Scholar

Sutkowski N, Conrad B, Thorley-Lawson DA and Huber BT: Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity. 15:579–589. 2001. View Article : Google Scholar

Karimi A, Sheervalilou R and Kahroba H: A new insight on activation of human endogenous retroviruses (HERVs) in malignant melanoma upon exposure to CuSO4. Biol Trace Elem Res. 191:70–74. 2019. View Article : Google Scholar

Alqahtani S, Promtong P, Oliver AW, He XT, Walker TD, Povey A, Hampson L and Hampson IN: Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines. Mutagenesis. 31:695–702. 2016. View Article : Google Scholar

Reiche J, Pauli G and Ellerbrok H: Differential expression of human endogenous retrovirus K transcripts in primary human melanocytes and melanoma cell lines after UV irradiation. Melanoma Res. 20:435–440. 2010.

Tsilimigras MC, Fodor A and Jobin C: Carcinogenesis and therapeutics: The microbiota perspective. Nat Microbiol. 2:170082017. View Article : Google Scholar

Simanshu DK, Nissley DV and McCormick F: RAS proteins and their regulators in human disease. Cell. 170:17–33. 2017. View Article : Google Scholar

Vieler M and Sanyal S: p53 Isoforms and their implications in cancer. Cancers (Basel). 10:2882018. View Article : Google Scholar

McLane LM, Abdel-Hakeem MS and Wherry EJ: CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 37:457–495. 2019. View Article : Google Scholar

Chan SL, Wong VW, Qin S and Chan HL: Infection and cancer: The case of hepatitis B. J Clin Oncol. 34:83–90. 2016. View Article : Google Scholar

Roden RBS and Stern PL: Opportunities and challenges for human papillomavirus vaccination in cancer. Nat Rev Cancer. 18:240–254. 2018. View Article : Google Scholar

Cianciolo GJ, Copeland TD, Oroszlan S and Snyderman R: Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science. 230:453–455. 1985. View Article : Google Scholar

Mangeney M, de Parseval N, Thomas G and Heidmann T: The full-length envelope of an HERV-H human endogenous retrovirus has immunosuppressive properties. J Gen Virol. 82:2515–2518. 2001. View Article : Google Scholar

Hummel J, Kämmerer U, Müller N, Avota E and Schneider-Schaulies S: Human endogenous retrovirus envelope proteins target dendritic cells to suppress T-cell activation. Eur J Immunol. 45:1748–1759. 2015. View Article : Google Scholar

Lv H, Han J, Liu J, Zheng J, Zhong D and Liu R: ISDTool: A computational model for predicting immunosuppressive domain of HERVs. Comput Biol Chem. 49:45–50. 2014. View Article : Google Scholar

Kraus B, Fischer K, Büchner SM, Wels WS, Löwer R, Sliva K and Schnierle BS: Vaccination directed against the human endogenous retrovirus-K envelope protein inhibits tumor growth in a murine model system. PLoS One. 8:e727562013. View Article : Google Scholar

Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin B, Frerich K, Garza JG, Shen J, Lin K, Yan P, et al: Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst. 104:189–210. 2012. View Article : Google Scholar

Kim HJ, Moon BI, Lee JW, Kim SC and Kim HJ: Age-related reduction of antibody response against the human endogenous retrovirus K envelope in women. Oncotarget. 7:17327–17337. 2016. View Article : Google Scholar

Mastrangelo G, Pavanello S, Fadda E, Buja A and Fedeli U: Yellow fever vaccine 17D administered to healthy women aged between 40 and 54 years halves breast cancer risk: An observational study. Eur J Cancer Prev. 27:303–309. 2018. View Article : Google Scholar

Zhou F, Krishnamurthy J, Wei Y, Li M, Hunt K, Johanning GL, Cooper LJ and Wang-Johanning F: Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras. Oncoimmunology. 4:e10475822015. View Article : Google Scholar

Wang Z, Zheng Y, Park HJ, Li J, Carr JR, Chen YJ, Kiefer MM, Kopanja D, Bagchi S, Tyner AL and Raychaudhuri P: Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther. 12:759–767. 2013. View Article : Google Scholar

von Lintig FC, Dreilinger AD, Varki NM, Wallace AM, Casteel DE and Boss GR: Ras activation in human breast cancer. Breast Cancer Res Treat. 62:51–62. 2000. View Article : Google Scholar

Lemaître C, Tsang J, Bireau C, Heidmann T and Dewannieux M: A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion. PLoS Pathog. 13:e10064512017. View Article : Google Scholar

Bjerregaard B, Holck S, Christensen IJ and Larsson LI: Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci. 63:1906–1911. 2006. View Article : Google Scholar

Duelli D and Lazebnik Y: Cell fusion: A hidden enemy? Cancer Cell. 3:445–448. 2003. View Article : Google Scholar

Anderson MJ and Stanbridge EJ: Tumor suppressor genes studied by cell hybridization and chromosome transfer. FASEB J. 7:826–833. 1993. View Article : Google Scholar

Köhler G and Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 256:495–497. 1975. View Article : Google Scholar

Li N, Li Y, Lv J, Zheng X, Wen H, Shen H, Zhu G, Chen TY, Dhar SS, Kan PY, et al: ZMYND8 reads the dual histone mark H3K4me1-H3K14ac to antagonize the expression of metastasis-linked genes. Mol Cell. 63:470–484. 2016. View Article : Google Scholar

Jin X, Xu XE, Jiang YZ, Liu YR, Sun W, Guo YJ, Ren YX, Zuo WJ, Hu X, Huang SL, et al: The endogenous retrovirus-derived long noncoding RNA TROJAN promotes triple-negative breast cancer progression via ZMYND8 degradation. Sci Adv. 5:eaat98202019. View Article : Google Scholar

Galiè M: RAS as supporting actor in breast cancer. Front Oncol. 9:11992019. View Article : Google Scholar

Kaufmann S, Sauter M, Schmitt M, Baumert B, Best B, Boese A, Roemer K and Mueller-Lantzsch N: Human endogenous retrovirus protein Rec interacts with the testicular zinc-finger protein and androgen receptor. J Gen Virol. 91:1494–1502. 2010. View Article : Google Scholar

Benešová M, Trejbalová K, Kovářová D, Vernerová Z, Hron T, Kučerová D and Hejnar J: DNA hypomethylation and aberrant expression of the human endogenous retrovirus ERVWE1/syncytin-1 in seminomas. Retrovirology. 14:202017. View Article : Google Scholar

Jiang B, Yang B, Wang Q, Zheng X, Guo Y and Lu W: lncRNA PVT1 promotes hepatitis B virus-positive liver cancer progression by disturbing histone methylation on the c-Myc promoter. Oncol Rep. 43:718–726. 2020.

de Souza CR, Leal MF, Calcagno DQ, Costa Sozinho EK, Borges Bdo N, Montenegro RC, Dos Santos AK, Dos Santos SE, Ribeiro HF, Assumpção PP, et al: MYC deregulation in gastric cancer and its clinicopathological implications. PLoS One. 8:e644202013. View Article : Google Scholar

Denne M, Sauter M, Armbruester V, Licht JD, Roemer K and Mueller-Lantzsch N: Physical and functional interactions of human endogenous retrovirus proteins Np9 and rec with the promyelocytic leukemia zinc finger protein. J Virol. 81:5607–5616. 2007. View Article : Google Scholar

Hanke K, Chudak C, Kurth R and Bannert N: The Rec protein of HERV-K(HML-2) upregulates androgen receptor activity by binding to the human small glutamine-rich tetratricopeptide repeat protein (hSGT). Int J Cancer. 132:556–567. 2013. View Article : Google Scholar

Armbruester V, Sauter M, Roemer K, Best B, Hahn S, Nty A, Schmid A, Philipp S, Mueller A and Mueller-Lantzsch N: Np9 protein of human endogenous retrovirus K interacts with ligand of numb protein X. J Virol. 78:10310–10319. 2004. View Article : Google Scholar

Shao X, Ding Z, Zhao M, Liu K, Sun H, Chen J, Liu X, Zhang Y, Hong Y and Li H and Li H: Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4. J Biol Chem. 292:20628–20643. 2017. View Article : Google Scholar

Fischer S, Echeverría N, Moratorio G, Landoni AI, Dighiero G, Cristina J, Oppezzo P and Moreno P: Human endogenous retrovirus np9 gene is over expressed in chronic lymphocytic leukemia patients. Leuk Res Rep. 3:70–72. 2014.

Hu Y, Chen Y, Douglas L and Li S: beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia. 23:109–116. 2009. View Article : Google Scholar

Polak R and Buitenhuis M: The PI3K/PKB signaling module as key regulator of hematopoiesis: Implications for therapeutic strategies in leukemia. Blood. 119:911–923. 2012. View Article : Google Scholar

Wu B, Gan Y, Xu Y, Wu Z, Xu G, Wang P, Wang C, Meng Z, Li M, Zhang J, et al: Identification of the novel Np17 oncogene in human leukemia. Aging (Albany NY). 12:2020.

Chen J, Foroozesh M and Qin Z: Transactivation of human endogenous retroviruses by tumor viruses and their functions in virus-associated malignancies. Oncogenesis. 8:62019. View Article : Google Scholar

Gabaev I, Williamson JC, Crozier TWM, Schulz TF and Lehner PJ: Quantitative proteomics analysis of lytic KSHV infection in human endothelial cells reveals targets of viral immune modulation. Cell Rep. 33:1082492020. View Article : Google Scholar

Wang-Johanning F, Li M, Esteva FJ, Hess KR, Yin B, Rycaj K, Plummer JB, Garza JG, Ambs S and Johanning GL: Human endogenous retrovirus type K antibodies and mRNA as serum biomarkers of early-stage breast cancer. Int J Cancer. 134:587–595. 2014. View Article : Google Scholar

Tokuyama M, Kong Y, Song E, Jayewickreme T, Kang I and Iwasaki A: ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. Proc Natl Acad Sci USA. 115:12565–12572. 2018. View Article : Google Scholar

Mullins CS and Linnebacher M: Endogenous retrovirus sequences as a novel class of tumor-specific antigens: An example of HERV-H env encoding strong CTL epitopes. Cancer Immunol Immunother. 61:1093–1100. 2012. View Article : Google Scholar

Wang-Johanning F, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK and Johanning GL: Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res. 68:5869–5877. 2008. View Article : Google Scholar

Kudo-Saito C, Yura M, Yamamoto R and Kawakami Y: Induction of immunoregulatory CD271⁺ cells by metastatic tumor cells that express human endogenous retrovirus H. Cancer Res. 74:1361–1370. 2014. View Article : Google Scholar

Humer J, Waltenberger A, Grassauer A, Kurz M, Valencak J, Rapberger R, Hahn S, Löwer R, Wolff K, Bergmann M, et al: Identification of a melanoma marker derived from melanoma-associated endogenous retroviruses. Cancer Res. 66:1658–1663. 2006. View Article : Google Scholar

Reis BS, Jungbluth AA, Frosina D, Holz M, Ritter E, Nakayama E, Ishida T, Obata Y, Carver B, Scher H, et al: Prostate cancer progression correlates with increased humoral immune response to a human endogenous retrovirus GAG protein. Clin Cancer Res. 19:6112–6125. 2013. View Article : Google Scholar

Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, et al: Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 162:974–986. 2015. View Article : Google Scholar

Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, Han H, Liang G, Jones PA, Pugh TJ, et al: DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 162:961–973. 2015. View Article : Google Scholar

Haffner MC, Taheri D, Luidy-Imada E, Palsgrove DN, Eich ML, Netto GJ, Matoso A, Nirschl TR, Zheng Q, Hicks JL, et al: Hypomethylation, endogenous retrovirus expression, and interferon signaling in testicular germ cell tumors. Proc Natl Acad Sci USA. 115:E8580–E8582. 2018. View Article : Google Scholar

Argaw-Denboba A, Balestrieri E, Serafino A, Cipriani C, Bucci I, Sorrentino R, Sciamanna I, Gambacurta A, Sinibaldi-Vallebona P and Matteucci C: HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features. J Exp Clin Cancer Res. 36:202017. View Article : Google Scholar

Saini SK, Ørskov AD, Bjerregaard AM, Unnikrishnan A, Holmberg-Thydén S, Borch A, Jensen KV, Anande G, Bentzen AK, Marquard AM, et al: Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers. Nat Commun. 11:56602020. View Article : Google Scholar

Tatkiewicz W, Dickie J, Bedford F, Jones A, Atkin M, Kiernan M, Maze EA, Agit B, Farnham G, Kanapin A and Belshaw R: Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: Enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines. Mob DNA. 11:92020. View Article : Google Scholar

Ficial M, Jegede OA, Sant'Angelo M, Hou Y, Flaifel A, Pignon JC, Braun DA, Wind-Rotolo M, Sticco-Ivins M, Catalano PJ, et al: Expression of T-cell exhaustion molecules and human endogenous retroviruses as predictive biomarkers for response to nivolumab in metastatic clear cell renal cell carcinoma. Clin Cancer Res. 30842020.

Siebenthall KT, Miller CP, Vierstra JD, Mathieu J, Tretiakova M, Reynolds A, Sandstrom R, Rynes E, Haugen E, Johnson A, et al: Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma. EBioMedicine. 41:427–442. 2019. View Article : Google Scholar