Abstract
Nasopharyngeal carcinoma (NPC) is a head and neck cancer prevalent throughout Southern China and Southeast Asia. Patient death following relapse after primary treatment remains all too common but the cause of NPC relapse is unclear. Clinical and epidemiological studies have revealed the high correlation among NPC development, Epstein-Barr virus (EBV) reactivation and host genomic instability. Previously, recurrent EBV reactivation was shown to cause massive genetic alterations and enhancement of tumor progression in NPC cells and these may be required for NPC relapse. Here, EBV BALF3 has the ability to induce micronuclei and DNA strand breaks. After recurrent expression of BALF3 in NPC cells, genomic copy number aberrations, determined by array-based comparative genomic hybridization, had accumulated to a significant extent and tumorigenic features, such as cell migration, cell invasion and spheroid formation, increased with the rounds of induction. In parallel experiments, cells after highly recurrent induction developed into larger tumor nodules than control cells when inoculated into NOD/SCID mice. Furthermore, RNA microarrays showed that differential expression of multiple cancer capability-related genes and oncogenes increased with recurrent BALF3 expression and these changes correlated with genetic aberrations. Therefore, EBV BALF3 is a potential factor that mediates the impact of EBV on NPC relapse.
Highlights
Nasopharyngeal carcinoma (NPC) is an endemic cancer, which is distributed predominantly through certain geographic areas and in particular racial/ethnic populations
The coding region of BALF3 in pEGFP-C1BALF3 was mutated by replacement of glycine 624 with alanine, with the result that the occurrence of micronuclei and H2AX phosphorylation induced by the G624A mutant was reduced to a significant extent, compared to the wildtype transfection (Figure 1C, D and G), confirming that Epstein-Barr virus (EBV) BALF3 could generate chromosome breakage and loss and double-strand breaks (DSBs)
Numerous clinical tests have shown that patients with NPC have EBV lytic gene products and IgA antibodies against EBV lytic antigens in tumor biopsies and sera, respectively; in addition, NPC tissues contain the linear form of viral DNA, which is consistent with the detection of replicative RNAs [65, 66]
Summary
Nasopharyngeal carcinoma (NPC) is an endemic cancer, which is distributed predominantly through certain geographic areas and in particular racial/ethnic populations. A reversal to increasing titers is seen in long-term survivors with relapse or metastasis [16,17,18, 20, 23]. These prospective and retrospective investigations suggest that the antibodies against EBV lytic antigens are indicative serological markers for the prognosis and diagnosis of NPC. EBV plays a critical role in the development of NPC
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