Human cytomegalovirus DNA and immediate early protein 1/2 are highly associated with glioma and prognosis
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Protein & Cell
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Dear Editor, Gliomas are the most common brain tumors in adults which encompass all primary central nervous system (CNS) tumors of glial cell origin. The World Health Organization (WHO) classifies gliomas into four grades based on the histologic/prognostic features. Because of the unclear etiology and pathogenesis, therapeutic efficacy and prognosis is poor. Viruses have been identified as causative factors in tumorigenesis. Among nine human herpesviruses (HHVs), Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are involved in the development of various cancers. Human cytomegalovirus (HCMV) components have been found to be present in a large proportion of glioblastoma (GBM) (Cobbs et al., 2002). HCMV establishes latency in T98G glioblastoma cells and latent HCMV can be reactivated (Cheng et al., 2017). It was also reported that HCMV potentially induces a functional mesenchymal-to-epithelial (MET) transition without affecting their viability in transformed breast carcinoma and glioma stem cells, which might encourage tumor colonization (Oberstein and Shenk 2017). HCMV has also be shown to be capable of activating oncogenic pathways in mammary epithelial cells (Kumar et al., 2018) and murine cytomegalovirus could promote murine GBM growth via pericyte recruitment and angiogenesis (Krenzlin et al., 2019). Besides a direct role, HCMV inhibits apoptosis and immediate early 1 protein (IE1) increases the malignancy of glioma cells through mediating mitogenicity and converting glioblastoma cells to a stemness phenotype. HCMV proteins US28, pp71, and glycoprotein B (gB) are also involved in gliomagenesis (Dziurzynski et al., 2012). Notably, the administration of valganciclovir, an
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antiviral used to treat HCMV infection, as an add-on to standard therapy resulted in a higher survival rate among GBM patients in a clinical trial (Soderberg-Naucler et al., 2013). Despite these findings, different viewpoints exist: several researchers consider HCMV components to be absent in GBM (Yamashita et al., 2014) and presented CMV DNA in GBM may be attributed to low-level contamination from adjacent leukocytes (Tang et al., 2015). Other studies consider that HCMV proteins and nucleic acids are present in gliomas, but not correlated with the tumor grade and prognosis (Ding et al., 2014). HCMV viral load and protein levels in glioma are extremely low and variable, which may lead to these incongruous and controversial results. The goal of the present study is to evaluate the correlation between HHVs and glioma in China, where the HCMV seroprevalence is over 90%. Samples from 378 patients (See Supplementary Materials) were investigated. DNAs of the nine HHVs were examined in paired peripheral whole blood and brain tissues. In peripheral blood HCMV DNA had the highest prevalence, however, no differences in DNAemia between high-grade glioma (HGG), low-grade glioma (LGG), or non-glioma (NG) groups were found for any of the nine HHVs tested (Fig. S1A). In brain tissues the preva
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