Potential role of oxidative stress-induced apoptosis in mediating chromosomal rearrangements in nasopharyngeal carcinoma

Abstract

BackgroundGenetic aberrations have been identified in nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains elusive. There are increasing evidences that the apoptotic nuclease caspase-activated deoxyribonuclease (CAD) is one of the players leading to translocation in leukemia. Oxidative stress, which has been strongly implicated in carcinogenesis, is a potent apoptotic inducer. Most of the NPC etiological factors are known to induce oxidative stress. Although apoptosis is a cell death process, cells possess the potential to survive apoptosis upon DNA repair. Eventually, the surviving cells may carry rearranged chromosomes. We hypothesized that oxidative stress-induced apoptosis may cause chromosomal breaks mediated by CAD. Upon erroneous DNA repair, cells that survive apoptosis may harbor chromosomal rearrangements contributing to NPC pathogenesis. This study focused on the AF9 gene at 9p22, a common deletion region in NPC. We aimed to propose a possible model for molecular mechanism underlying the chromosomal rearrangements in NPC.ResultsIn the present study, we showed that hydrogen peroxide (H2O2) induced apoptosis in NPC (HK1) and normal nasopharyngeal epithelial (NP69) cells, as evaluated by flow cytometric analyses. Activity of caspases 3/7 was detected in H2O2-treated cells. This activity was inhibited by caspase inhibitor (CI). By nested inverse polymerase chain reaction (IPCR), we demonstrated that oxidative stress-induced apoptosis in HK1 and NP69 cells resulted in cleavages within the breakpoint cluster region (BCR) of the AF9 gene. The gene cleavage frequency detected in the H2O2-treated cells was found to be significantly higher than untreated control. We further found that treatment with CI, which indirectly inhibits CAD, significantly reduced the chromosomal breaks in H2O2-cotreated cells. Intriguingly, a few breakpoints were mapped within the AF9 region that was previously reported to translocate with the mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemia (ALL) patient.ConclusionsIn conclusion, our findings suggested that oxidative stress-induced apoptosis could be one of the mechanisms underlying the chromosomal rearrangements in NPC. CAD may play an important role in chromosomal cleavages mediated by oxidative stress-induced apoptosis. A potential model for oxidative stress-induced apoptosis mediating chromosomal rearrangements in NPC is proposed.

Osthole induces human nasopharyngeal cancer cells apoptosis through Fas–Fas ligand and mitochondrial pathway

“…Death receptor ligands characteristically initiate signaling through receptor oligomerization, resulting in the recruitment of specialized adaptor proteins and activation of caspase cascades . NPC‐039 cells were treated with different concentrations (0, 10, 20, 40, and 80 μM) of osthole for 48 h. Osthole increased the expression of Fas, FADD, TNF‐R1, TNF‐R2, DcR2, RIP, and DR5 (Figure ).…”

Caspase-3 as an important factor in the early cytotoxic effect of nickel on oral mucosa cells in patients treated orthodontically

“…It has been well established that caspase-3 is necessary for apoptotic chromatin condensation and DNA fragmentation [19]. Furthermore, it has been demonstrated that the activation of caspase-3 is associated with oxidative stress [20,21]. Soesetijo et al have recently demonstrated high apoptosis of gingival fibroblasts treated with nickel-containing artificial saliva [1].…”

­ Comprehensive analysis of key genes associated with ceRNA networks in nasopharyngeal carcinoma based on bioinformatics analysis

“…The highly expressed miRNA hsa-miR-6088 and the lowly expressed miRNA hsa-let-7f-1-3p from the above study were also found in our ceRNA networks. We also identi ed hsa-miR-29a-3p and hsa-miR-103a-3p as DEmiRNAs, which were recently found to act as circulating biomarkers of NPC, with fairly good diagnostic accuracy for detecting NPC as compared with controls (area under the curve > 0.7) [38] Several studies have reported on the chromosomal aberrations involved in the carcinogenesis of NPC, including chromosomal gains or losses [41,42], loss of heterozygosity [43], and chromosomal rearrangements [44], and chromosomal imbalances [45]. In one study, loss of heterozygosity on 3p was observed in 95%-100% of primary NPC specimens and almost 75% of pre-cancerous lesions [43].…”

“…Tan et al hypothesized that apoptosis induced by oxidative stress may lead to CAD-mediated chromosomal breakage. After incorrect DNA repair, cells that survive apoptosis may carry chromosomal rearrangements, leading to the tumorigenesis of NPC [44]. To investigate common genetic variations in NPC, Natasya et al screened out 7 cases of NPC in the Malaysian population by the comparative genomic hybridization (CGH) technology.…”