Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

Oncogene volume 26, pages 4226–4233 (2007)Cite this article

Abstract

Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced proliferation, induced differentiation and reprogrammed gene expression in human tumorigenic cell lines. Moreover, the antiretroviral drug efavirenz antagonized tumor progression in animal models in vivo. To get insight into the role of retroelements in tumorigenesis, we have now produced two cell lines derived from A-375 melanoma, in which the expression of either L1 retrotransposon, or HERV-K endogenous retrovirus, was stably suppressed by RNAi. Compared to the parental A-375 cell line, cells with stably interfered L1 expression show a lower proliferation rate, a differentiated morphology and lower tumorigenicity when inoculated in nude mice. L1 silencing modulates expression of several genes and, unexpectedly, also downregulates HERV-K expression. In HERV-K interfered cells, instead, L1 expression was unaffected, and cell proliferation and differentiation remained unchanged compared to parental A-375 cells.In vivo, however, their tumorigenic potential was found to be reduced after inoculation in nude mice. These results suggest that L1 and HERV-K play specific and distinct roles in cell transformation and tumor progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Batzer MA, Deininger PL . (2002). Alu repeats and human genomic diversity. Nature 3: 370–379.

    CAS  Google Scholar 

  • Beraldi R, Pittoggi C, Sciamanna I, Mattei E, Spadafora C . (2006). Expression of LINE-1 retroposons is essential for murine preimplantation development. Mol Reprod Dev 73: 279–287.

    Article  CAS  Google Scholar 

  • Blaise S, Mangeney M, Heidmann T . (2001). The envelope of Mason–Pfizer monkey virus has immunosuppressive properties. J Gen Virology 82: 1597–1600.

    Article  CAS  Google Scholar 

  • Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV et al. (2003). Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA 100: 5280–5285.

    Article  CAS  Google Scholar 

  • Dent P, Yacoub A, Grant S, Curiel DT, Fisher PB . (2005). MDA-7/IL-24 regulates proliferation, invasion and tumor cell radiosensitivity: a new cancer therapy? J Cell Biochem 95: 712–719.

    Article  CAS  Google Scholar 

  • Ergun S, Buschmann C, Heukeshoven J, Dammann K, Schnieders F, Lauke H et al. (2004). Cell type-specific expression of LINE-1 open reading frames 1 and 2 in fetal and adult human tissues. J Biol Chem 279: 27753–27763.

    Article  Google Scholar 

  • Farag SS, Caligiuri MA . (2006). Human natural killer cell development and biology. Blood Rev 20: 123–137.

    Article  CAS  Google Scholar 

  • Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP . (2002). Nuclear lamins: building blocks of nuclear architecture. Genes Dev 16: 533–547.

    Article  CAS  Google Scholar 

  • Gruenbaum Y, Goldman RD, Meyuhas R, Mills E, Margalit A, Fridkin A et al. (2003). The nuclear lamina and its functions in the nucleus. Int Rev Cytol 226: 1–62.

    Article  CAS  Google Scholar 

  • Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL . (2005). The nuclear lamina comes of age. Nat Rev 6: 21–31.

    Article  CAS  Google Scholar 

  • Han JS, Boeke JD . (2005). LINE-1 retrotransposons: modulators of quantity and quality of mammalian gene expression? BioEssays 27: 775–784.

    Article  CAS  Google Scholar 

  • Hasui M, Saikawa Y, Miura M, Takano N, Ueno Y, Yachie A et al. (1989). Effector and precursor phenotypes of lymphokine-activated killer cells in mice with severe combined immunodeficiency (scid) and athymic (nude) mice. Cellular Immun 120: 230–239.

    Article  CAS  Google Scholar 

  • Humer J, Waltenberger A, Grassauer A, Kurz M, Valencak J, Rapberger R . (2006). Identification of a melanoma marker derived from melanoma-associated endogenous retroviruses. Cancer Res 66: 1658–1663.

    Article  CAS  Google Scholar 

  • INTERNATIONAL HUMAN GENOME CONSORTIUM (2001). Initial sequencing and analysis of the human genome. Nature 409: 860–921.

    Article  Google Scholar 

  • Kazazian HH . (2004). Mobile elements: drivers of genome evolution. Science 303: 1626–1632.

    Article  CAS  Google Scholar 

  • Landriscina M, Fabiano A, Altamura S, Bagala C, Piscazzi A, Cassano A et al. (2005). Reverse transcriptase inhibitors downregulate cell proliferation in vitro and in vivo and restore TSH signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab 90: 5663–5671.

    Article  CAS  Google Scholar 

  • Mangeney M, Heidmann T . (1998). Tumor cells expressing a retroviral envelope escare immune rejection in vivo. Proc Natl Acad Sci USA 95: 14920–14925.

    Article  CAS  Google Scholar 

  • Mangeney M, Pothlichet J, Renard M, Ducos B, Heidmann T . (2005). Endogenous retrovirus expression is required for murine melanoma tumor growth in vivo. Cancer Res 65: 2588–2591.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Mangiacasale R, Pittoggi C, Sciamanna I, Careddu A, Mattei E, Lorenzini R et al. (2003). Exposure of normal and transformed cells to nevirapine, a Reverse Transcriptase inhibitor, reduces cell growth and promotes differentiation. Oncogene 22: 2750–2761.

    Article  CAS  Google Scholar 

  • Nickerson JA, Krockmalnic G, Wan KM, Penman S . (1997). The nuclear matrix revealed by eluting chromatin from a cross-linked nucleus. Proc Natl Acad Sci USA 94: 4446–4450.

    Article  CAS  Google Scholar 

  • Orgel LE, Crick FH . (1980). Selfish DNA: the ultimate parasite. Nature 284: 604–607.

    Article  CAS  Google Scholar 

  • Pittoggi C, Sciamanna I, Mattei E, Beraldi R, Lobascio AM, Mai A et al. (2003). Role of endogenous reverse transcriptase in murine early embryo development. Mol Reprod Dev 66: 225–236.

    Article  CAS  Google Scholar 

  • Quia F, Zhang ZC, Wu XF, Li YP, Xu Q . (2005). Interaction between integrin alpha(5) and fibronectin is required for metastasis of B16F10 melanoma cells. Biochem Biophys Res Commun 333: 1269–1275.

    Article  Google Scholar 

  • Ross DA, Laing JH, Sanders R, Wilson GD . (2006). Long term follow-up of c-myc, p53 and proliferation measurements in malignant melanoma. Eur J Surg Oncol 32: 80–84.

    Article  CAS  Google Scholar 

  • Sauter ER, Yeo UC, Von Stemm A, Zhu W, Litwin S, Tichansky DS et al. (2002). Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res 62: 3200–3206.

    CAS  PubMed  Google Scholar 

  • Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R et al. (2005). Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 24: 3923–3931.

    Article  CAS  Google Scholar 

  • Shapiro JA, von Sternberg R . (2005). Why repetitive DNA is essential to genome function. Biol Rev 80: 1–24.

    Article  Google Scholar 

  • Sinibaldi-Vallebona P, Lavia P, Garaci E, Spadafora C . (2006). A role for endogenous reverse transcriptase in tumorigenesis and as a target in differentiating cancer therapy. Genes Chromosomes Cancer 45: 1–10.

    Article  CAS  Google Scholar 

  • Umekita Y, Hiipakka RA, Koknotis JM, Shutsung L . (1996). Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride. Proc Natl Acad Sci USA 93: 11802–11807.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr R Loewer for critical reading of the manuscript. We acknowledge the skillful contribution of A Felici for assistance with animal work. This work was supported by Istituto Superiore di Sanità (grants R002, 501/1, 501/2 to CS) and, in part, by grants SCHU 1014/2-1 and SCHU 1014/2-2 of the Deutsche Forschugsgemeinschaft to GGS.

Author information

Authors and Affiliations

  1. Istituto Superiore di Sanità, Rome, Servizio BGSA, Italy

    E Oricchio, I Sciamanna, R Beraldi & C Spadafora

  2. Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Rome, Italy

    E Oricchio

  3. Department of Pediatrics and Obstetrician, University of Siena, Siena, Italy

    R Beraldi

  4. Heinrich-Pette Institüte fur Experimentelle Virologie und Immunologie an der Universität, Hamburg, Germany

    G V Tolstonog

  5. Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, Germany

    G G Schumann

Authors
  1. E Oricchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Sciamanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Beraldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G V Tolstonog
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G G Schumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Spadafora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Spadafora.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oricchio, E., Sciamanna, I., Beraldi, R. et al. Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression. Oncogene 26, 4226–4233 (2007). https://doi.org/10.1038/sj.onc.1210214

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210214

Keywords

This article is cited by

Search

Advanced search

Quick links