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Human endogenous retroviruses env gene expression and long terminal repeat methylation in colorectal cancer patients

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Abstract

Human endogenous retroviruses (HERV) are remnants of exogenous retroviral infections, representing 8% of the human genome. Their regulation is based on the DNA methylation of promoters, the long terminal repeats (LTRs). Transcripts from HERV have been associated with cancers, but reports concerning HERV expression in colorectal cancer remain sporadic. Sixty-three patients with advanced stages of colorectal cancer were enrolled in this study. The expressions of HERV env gene, and HERV-H, -K, -R and -P LTRs and Alu, LINE-1 methylation levels, were investigated in the tumor, normal adjacent tissues, and, where possible, blood and plasmatic extracellular vesicles (EVs). Associations among HERV env expression, methylation status and clinical characteristics were evaluated. No differences were observed in HERV env gene expression levels among the clinical specimens, while Alu, LINE-1, HERV-H and -K LTRs were demethylated in the tumor compared to the normal adjacent tissues (p < 0.05).The HERV env gene was expressed in the EVs at of 54% (-H), 38% (-K), 31% (-R) patients. Association was not found between HERV env expression and LTR methylation, but significant higher expression of HERV-P and -R env was found in tumor tissues arising from the right colon. Our findings do not demonstrate significant overexpression of the studied HERV in colorectal cancer, but their association with tumor localization and specificity of the changes in DNA methylation of retroelements are shown. HERV sequences were packaged in the EVs and might be transferred from one cell to another.

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Funding

The study was supported by the Italian Ministry of University—PRIN 2015 to Pasquale Ferrante; Contract Grant Number 2015w729wh and by the University of Milan—Piano Sostegno alla Ricerca (PSR) 2017 and 2018, to Serena Delbue.

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Author notes

  1. Maria Dolci and Chiara Favero have equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Via Carlo Pascal, 36, 20133, Milan, Italy

    Maria Dolci, Sonia Villani, Lucia Signorini, Sarah D’Alessandro, Pasquale Ferrante & Serena Delbue

  2. EPIGET - Epidemiology, Epigenetics and Toxicology Lab, Department of Clinical Sciences and Community Health, University of Milan, Via San Barnaba 8, Milan, Italy

    Chiara Favero & Valentina Bollati

  3. Department of Preventive Medicine, Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Via San Barnaba 8, Milan, Italy

    Letizia Tarantini & Valentina Bollati

  4. Hematology Unit, ASST Valle Olona, Ospedale di Circolo di Busto Arsizio, Via Arnaldo da Brescia 3, Busto Arsizio, Italy

    Marco Bregni

  5. General Surgery Unit, Istituto Clinico Città Studi, Via Jommelli 19, Milan, Italy

    Alberto Della Valle

  6. Pathology Unit, ASST Valle Olona, Ospedale di Circolo di Busto Arsizio, Via Arnaldo da Brescia 3, Busto Arsizio, Italy

    Filippo Crivelli

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  1. Maria Dolci
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Correspondence to Serena Delbue.

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The patients included in the study signed the informed consent after Institutional Ethics Committee approval was obtained (Ethical Committee Istituto Clinico Città Studi, Ospedale Maggiore Policlinico Milano, Protocol Number 683_2017bis). The study was performed in accordance with the Declaration of Helsinki.

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Dolci, M., Favero, C., Tarantini, L. et al. Human endogenous retroviruses env gene expression and long terminal repeat methylation in colorectal cancer patients. Med Microbiol Immunol 209, 189–199 (2020). https://doi.org/10.1007/s00430-020-00662-6

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