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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

  • Alessandro Giovinazzo
  • Emanuela Balestrieri
  • Vita Petrone
  • Ayele Argaw-Denboba
  • Chiara Cipriani
  • Martino Tony Miele
  • Sandro Grelli
  • Paola Sinibaldi-Vallebona
  • Claudia MatteucciEmail author
Original Article

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.

Keywords

Endogenous retroviruses Cancer microenvironment Phenotype switching Embryonic transcription factors Antiretroviral drugs Cancer hallmarks 

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

Notes

Acknowledgments

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

Authors’ 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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12307_2019_231_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 24 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Alessandro Giovinazzo
    • 1
  • Emanuela Balestrieri
    • 1
  • Vita Petrone
    • 1
  • Ayele Argaw-Denboba
    • 2
  • Chiara Cipriani
    • 1
    • 3
  • Martino Tony Miele
    • 1
  • Sandro Grelli
    • 1
  • Paola Sinibaldi-Vallebona
    • 1
    • 4
  • Claudia Matteucci
    • 1
    Email author
  1. 1.Department of Experimental Medicine“Tor Vergata” University of RomeRomeItaly
  2. 2.European Molecular Biology Laboratory (EMBL), Adriano Buzzati-Traverso CampusRomeItaly
  3. 3.Department of UrologySan Carlo di Nancy Hospital - GVM Care and ResearchRomeItaly
  4. 4.National Research CouncilInstitute of Translational PharmacologyRomeItaly

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