Abstract
BackgroundOxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal carcinoma (NPC). Cells that are under oxidative stress may undergo apoptosis. We have previously demonstrated that oxidative stress-induced apoptosis could be a potential mechanism mediating chromosome breakages in nasopharyngeal epithelial cells. Additionally, caspase-activated DNase (CAD) may be the vital player in mediating the chromosomal breakages during oxidative stress-induced apoptosis. Chromosomal breakage occurs during apoptosis and chromosome rearrangement. Chromosomal breakages tend to cluster in certain regions, such as matrix association region/scaffold attachment region (MAR/SAR). We hypothesised that oxidative stress-induced apoptosis may result in chromosome breaks preferentially at the MAR/SAR sites. The AF9 gene at 9p22 was targeted in this study because 9p22 is a deletion site commonly found in NPC.ResultsBy using MAR/SAR recognition signature (MRS), potential MAR/SAR sites were predicted in the AF9 gene. The predicted MAR/SAR sites precisely match to the experimentally determined MAR/SARs. Hydrogen peroxide (H2O2) was used to induce apoptosis in normal nasopharyngeal epithelial cells (NP69) and NPC cells (HK1). Nested inverse polymerase chain reaction was employed to identify the AF9 gene cleavages. In the SAR region, the gene cleavage frequency of H2O2-treated cells was significantly higher than that of the non-treated cells. A few chromosomal breakages were detected within the AF9 region which was previously found to be involved in the mixed lineage leukaemia (MLL)-AF9 translocation in an acute lymphoblastic leukaemia patient. As for the non-SAR region, no significant difference in the gene cleavage frequency was found between the untreated control and H2O2-treated cells. Furthermore, H2O2-induced cleavages within the SAR region were reduced by caspase-3 inhibitor, which indirectly inhibits CAD.ConclusionsThese results reaffirm our previous findings that oxidative stress-induced apoptosis could be one of the potential mechanisms underlying chromosome breakages in nasopharyngeal epithelial cells. MAR/SAR may play a vital role in defining the location of chromosomal breakages mediated by oxidative stress-induced apoptosis, where CAD is the major nuclease.
Highlights
Oxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal car‐ cinoma (NPC)
In silico prediction of matrix association region/scaffold attachment region (MAR/SAR) By using MAR/SAR recognition signature (MRS), 29 possible MAR/SAR sites were predicted in the AF9 gene
Our results clearly demonstrate that oxidative stressinduced apoptosis results in the AF9 gene cleavages within the region that contains MAR/SAR
Summary
Oxidative stress is known to be involved in most of the aetiological factors of nasopharyngeal car‐ cinoma (NPC). We have previously demonstrated that oxidative stress-induced apoptosis could be a potential mechanism mediating chromosome breakages in naso‐ pharyngeal epithelial cells. Caspase-activated DNase (CAD) may be the vital player in mediating the chro‐ mosomal breakages during oxidative stress-induced apoptosis. We hypothesised that oxidative stress-induced apoptosis may result in chromosome breaks preferentially at the MAR/SAR sites. A case–control study of NPC among Malaysian Chinese has reported that salted fish consumption during childhood was a significant risk factor for developing NPC [3]. Chinese salted fish was found to cause nasal cavity tumours in rats [5, 6]. These findings suggested the presence of carcinogenic substances in salted fish. Chronic inflammation of sinonasal tract has been increasingly recognised as a risk factor for NPC [13, 14]
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