Abstract
Neuroblastoma (NB) is the commonest solid tumor outside the central nervous system in infancy and childhood with a unique biological heterogeneity. In patients with advanced, metastasizing neuroblastoma, treatment failure and poor prognosis is often marked by resistance to chemo- or immunotherapy. Thus, identification of robust biomarkers seems essential for understanding tumor progression and developing effective therapy. Here, we have studied the expression of human endogenous retroviruses (HERV) as potential targets in NB cell lines during stem-cell medium-induced microenvironmental change. Quantitative PCR revealed that relative expression of the HERV-K family and HERV-W1 ENV were increased in all three NB cell lines after incubation in stem-cell medium. Virus transcriptome analyses revealed the transcriptional activation of three endogenous retrovirus elements: HERV-R ENV (ERV3-1), HERV-E1 and HERV-Fc2 ENV (ERVFC1-1). Known malignancy markers in NB, e.g. proto-oncogenic MYC or MYCN were expressed highly heterogeneously in the three investigated NB cell lines with up-regulation of MYC and MYCN upon medium-induced microenvironmental change. In addition, SiMa cells exclusively showed a phenotype switching from loosely-adherent monolayers to low proliferating grape-like cellular aggregates, which was accompanied by an enhanced CD133 expression. Interestingly, the overexpression of HERV was associated with a significant elevation of immune checkpoint molecule CD200 in both quantitative PCR and RNA-seq analysis suggesting tumor escape mechanism in NB cell lines after incubation in serum-free stem cell medium.
Highlights
In the course of evolution, a large number of retroviral elements have entered the genome of vertebrates
No significant regulation was observed for human endogenous retroviruses (HERV)-Fc1 ENV, while the expression was comparatively low with CT values around 30
We have investigated the expression of HERV as potential targets in NB cell lines during stem-cell medium-induced microenvironmental change by RT-qPCR and RNA-seq
Summary
In the course of evolution, a large number of retroviral elements have entered the genome of vertebrates. In addition to the usual increase in autoreactive antibodies in the course of activation of the immune system [12], abnormally expressed HERV-W ENV has been shown to trigger inflammatory cascades including polyclonal activation of T lymphocytes [reviewed in [13]] Another HERV that was associated more recently with autoimmune disorders is the ENV of HERV-Fc1 (NCBI accession no.: XM_011531085.2) [14, 15]. In the course of focusing on individualized targeted therapy for more effective treatment, modulation of tumor microenvironment seems to be crucial [33, 34] In this context, lack of immunotherapeutic targets, like programmed cell death ligand-1 (PD-L1), in CD24 overexpressing NB, as well as amplification of multidrug resistance-associated genes and overexpression of immune checkpoint molecule CD200 in NB is of particular interest [35,36,37,38]
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