Abstract
Human cytomegalovirus (HCMV), a widespread beta-herpes virus, infects a high percentage of gliomas. HCMV is specifically detected in human gliomas at a low level of expression raises the possibility that it may regulate the malignant phenotype in a chronic manner. Although HCMV is not recognized as an oncogenic virus, it might dysregulate signaling pathways involved in initiation and promotion of malignancy.Here, our immunohistochemical staining reveals that nucleus staining of the HCMV 86-kDa immediate-early protein (IE86) is markedly increased in GBM (58.56%) compared with that in nontumorous samples (4.20%) and low-grade glioma(19.56%). IE86 staining positively correlates with the staining of activating transcription factor 5 (ATF5) which is essential for glioma cell viability and proliferation suggesting that HCMV IE86 could have important implications in glioma biology. Moreover, we find that the IE86 overexpression enhances glioma cell's growth in vitro and in vivo. We demonstrate that IE86 protein physically interacts with, and acetylates ATF5 thereby promoting glioma cell survival. Therefore, our findings illustrate the biological significance of HCMV infection in accelerating glioma progression, and provide novel evidence that HCMV infection may serve as a therapeutic target in human glioma.
Highlights
Malignant gliomas which character as invasive, aggressive, and neurologically destructive are considered one of the deadly human cancers
To confirm the existence of Human cytomegalovirus (HCMV) in gliomas and determine if there is a relationship between activating transcription factor 5 (ATF5) expression and HCMV infection, 58 paraffin-embedded glioma sections were performed for immunohistochemical staining
Similar to the pattern we observed for immediateearly protein 86 (IE86) expression, we found ATF5 protein high expression in tumor nucleus and cytoplasm of glioma tissues than normal tissues (Figure 1A)
Summary
Malignant gliomas which character as invasive, aggressive, and neurologically destructive are considered one of the deadly human cancers. Our previous work has demonstrated that neural stem cells are permissive to human cytomegalovirus (HCMV) infection, resulting in abnormal differentiation or inhibition of differentiation into normal astrocytes [6]. This result was consistent with previously published studies [7, 8]. HCMV infection induced glioma cancer stem cells (GCSCs) phenotypes which express the same marker CD133 with neural stem cells. Several reports have confirmed that HCMV viral genes and proteins expression were detected in most GBM cells but not in surrounding normal brain, or other neuropathologies, indicating a potential association between gliomas and HCMV infection [10,11,12]
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