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The Concomitant Expression of Human Endogenous Retroviruses and Embryonic Genes in Cancer Cells under Microenvironmental Changes is a Potential Target for Antiretroviral Drugs

  • Original Article
  • Published:
Cancer Microenvironment

Abstract

In our genomes there are thousands of copies of human endogenous retroviruses (HERVs) originated from the integration of exogenous retroviruses that infected germ line cells millions of years ago, and currently an altered expression of this elements has been associated to the onset, progression and acquisition of aggressiveness features of many cancers. The transcriptional reactivation of HERVs is mainly an effect of their responsiveness to some factors in cell microenvironment, such as nutrients, hormones and cytokines. We have already demonstrated that, under pressure of microenvironmental changes, HERV-K (HML-2) activation is required to maintain human melanoma cell plasticity and CD133+ cancer stem cells survival. In the present study, the transcriptional activity of HERV-K (HML-2), HERV-H, CD133 and the embryonic transcription factors OCT4, NANOG and SOX2 was evaluated during the in vitro treatment with antiretroviral drugs in cells from melanoma, liver and lung cancers exposed to microenvironmental changes. The exposure to stem cell medium induced a phenotype switching with the generation of sphere-like aggregates, characterized by the concomitant increase of HERV-K (HML-2) and HERV-H, CD133 and embryonic genes transcriptional activity. Although with heterogenic response among the different cell lines, the in vitro treatment with antiretroviral drugs affected HERVs transcriptional activity in parallel with the reduction of CD133 and embryonic genes expression, clonogenic activity and cell growth, accompanied by the induction of apoptosis. The responsiveness to antiretroviral drugs treatment of cancer cells with stemness features and expressing HERVs suggests the use of these drugs as innovative approach to treat aggressive tumours in combination with chemotherapeutic/radiotherapy regimens.

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Abbreviations

AZT:

Azidothymidine

EFV:

Efavirenz

CAFs:

Cancer associated fibroblasts

CTR:

Control

CSCs:

Cancer stem cells

DNMTi:

DNA methyltransferase inhibitors

ECM:

Extracellular matrix

Env:

Envelope

FBS:

Fetal bovine serum

GUSB:

Beta-glucuronidase

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HDACi:

Histone deacetylase inhibitors

HERVs:

Human endogenous retroviruses

hESC:

Human embryonic stem cells

HML-2:

Human-(mouse mammary tumor virus)-like-2

IFN:

Interferon

iPSC:

Induced pluripotent stem cells

LTRs:

Long terminal repeats

NANOG:

DNA binding homeobox transcription factor

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NNRTI:

Non-nucleoside reverse transcriptase inhibitor

NRTI:

Nucleoside reverse-transcriptase inhibitor

OCT4:

Octamer-binding transcription factor 4

SM:

Standard medium

RT:

Reverse-transcriptase

SOX2:

Sex determining region Y-box 2 transcription factor

TAMs:

Tumor-associated macrophages

TME:

Tumor microenvironment

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Acknowledgments

This project was supported by the Italian Ministry of University and Research (Research Projects of National Interest), grant no. 2010PHT9NF_001.

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Authors and Affiliations

  1. Department of Experimental Medicine, “Tor Vergata” University of Rome, Via Montpellier, 1, 00133, Rome, Italy

    Alessandro Giovinazzo, Emanuela Balestrieri, Vita Petrone, Chiara Cipriani, Martino Tony Miele, Sandro Grelli, Paola Sinibaldi-Vallebona & Claudia Matteucci

  2. European Molecular Biology Laboratory (EMBL), Adriano Buzzati-Traverso Campus, Monterotondo, Rome, Italy

    Ayele Argaw-Denboba

  3. Department of Urology, San Carlo di Nancy Hospital - GVM Care and Research, Rome, Italy

    Chiara Cipriani

  4. National Research Council, Institute of Translational Pharmacology, Rome, Italy

    Paola Sinibaldi-Vallebona

Authors
  1. Alessandro Giovinazzo
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  2. Emanuela Balestrieri
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  3. Vita Petrone
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  4. Ayele Argaw-Denboba
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  6. Martino Tony Miele
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  7. Sandro Grelli
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  8. Paola Sinibaldi-Vallebona
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  9. Claudia Matteucci
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Contributions

CM, EB and PSV conceived and designed the study. CM, EB, AAD and AG conceived and designed the experiments. AG, VP, AAD performed the experiments. CM, AG, EB, VP analysed and interpreted the data. CC, MTM supported the experiments and helped to draft the manuscript. SG contributed with conceptualisation the study and critical revision of manuscript. CM, AG, EB and PSV wrote the manuscript. MTM provided the linguistic assistance. PSV and CM provided the financial support and supervised laboratorial processes. All the authors read and approved the final version of the manuscript.

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Correspondence to Claudia Matteucci.

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Giovinazzo, A., Balestrieri, E., Petrone, V. et al. The Concomitant Expression of Human Endogenous Retroviruses and Embryonic Genes in Cancer Cells under Microenvironmental Changes is a Potential Target for Antiretroviral Drugs. Cancer Microenvironment 12, 105–118 (2019). https://doi.org/10.1007/s12307-019-00231-3

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