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Fig. 10 | BMC Cancer

Fig. 10

From: Bile acids at neutral and acidic pH induce apoptosis and gene cleavages in nasopharyngeal epithelial cells: implications in chromosome rearrangement

Fig. 10

A proposed model for BA-induced apoptosis in mediating chromosome rearrangements in NPC. Exposure of nasopharyngeal epithelial cells to BA triggers intracellular ROS generation. The effect of BA in triggering ROS production is enhanced by acid through synergistic mechanisms. Increased ROS level induces PS externalisation and MMP loss. The former is acting as the apoptotic signalling which activates the downstream cascade, whereas the latter leads to MPT which in turn provokes the release of proapoptotic proteins such as cytochrome c. Subsequently, the main effector, caspase-3 is activated and cleaves the ICAD which possesses two caspase-3 cleavage sites. Once CAD is released from its chaperone ICAD, it enters the nucleus to cleave the DNA and causes DNA fragmentation. Cells may evade apoptosis and recover upon DNA repair. However, imprecise DNA repair may cause chromosome rearrangements in surviving cells. Repeated exposure to BA and acid (i.e. gastric duodenal refluxate) may increase the rate of mutations. The genomic instability may be exacerbated by chronic inflammation of sinonasal tissue which is repeatedly exposed to gastric duodenal refluxate. This is due to the fact that ROS production, apoptotic signalling and DNA damage may also be provoked by the inflammatory response. The cytotoxicity and genotoxicity of BA, especially in combination of acid, may therefore contribute to chromosome rearrangements in NPC

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