title: Human herpes simplex viruses in benign and malignant thyroid tumours.
abstract: To test the hypothesis that herpes viruses may have a role in thyroid neoplasia, we analysed thyroid tissues from patients with benign (44) and malignant (65) lesions for HSV1 and HSV2 DNA. Confirmatory studies included direct sequencing, analysis of viral gene expression, and activation of viral-inducible signalling pathways. Expression of viral entry receptor nectin-1 was examined in human samples and in cancer cell lines. In vitro experiments were performed to explore the molecular mechanisms underlying thyroid cancer cell susceptibility to HSV. HSV DNA was detected in 43/109 (39.4%) examined samples. HSV capsid protein expression correlated with HSV DNA status. HSV-positive tumours were characterized by activation of virus-inducible signalling such as interferon-beta expression and nuclear NFkappaB expression. Lymphocyte infiltration and oncocytic cellular features were common in HSV-positive tumours. HSV1 was detected with the same frequency in benign and malignant thyroid tumours. HSV2 was significantly associated with papillary thyroid cancer and the presence of lymph node metastases. The expression of HSV entry receptor nectin-1 was increased in thyroid tumours compared to normal thyroid tissue and further increased in papillary thyroid cancer. Nectin-1 expression was detected in all examined thyroid cancer cell lines. Nectin-1 expression in cancer cells correlated with their susceptibility to HSV. Inhibition of PI3K/AKT or MAPK/ERK signalling did not affect the level of nectin-1 expression but decreased thyroid cancer cell susceptibility to HSV. These findings showed that HSV is frequently detected in thyroid cancer. During tumour progression, thyroid cells acquire increased susceptibility to HSV due to increased expression of viral entry mediator nectin-1 and activation of mitogenic signalling in cancer cells.
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Jensen
authors.forename: Aneeta
authors.initials: A
authors.lastname: Patel
authors.forename: Alexander
authors.initials: A
authors.lastname: Larin
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoperia
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Andrew
authors.initials: A
authors.lastname: Bauer
authors.forename: Kevin
authors.initials: K
authors.lastname: Yim
authors.forename: Val
authors.initials: V
authors.lastname: Hemming
authors.forename: Vasyl
authors.initials: V
authors.lastname: Vasko
mesh_terms: D000328:Adult; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D000075983:Nectins; D013961:Thyroid Gland / Q000378:metabolism / Q000821:virology; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000821:virology*
chemical_list: D015815:Cell Adhesion Molecules; D004279:DNA, Viral; C000619010:NECTIN1 protein, human; D016328:NF-kappa B; D000075983:Nectins; D016899:Interferon-beta