Indeed, work in our own laboratory has shown that overexpression of cytoglobin reduces levels of chemically-induced reactive oxygen species and affords protection from pro-oxidant induced injury. In further support for a role in detoxification of ROS, it has been reported that cytoglobin has peroxidase activity. Interestingly, more recently it has been reported that ferric cytoglobin has pseudo-peroxidase activity against lipids, suggesting that, under conditions of oxidative stress, turnover of lipid based cell signalling molecules may also be part of a cytoglobin-dependent antioxidant response. Furthermore, another vertebrate globin, globin X, has been found to be membrane associated and possibly involved in protection of lipids from (-)-Tetramisole oxidation. Intriguingly, in addition to the possible roles discussed above, the cytoglobin gene is also a candidate tumour suppressor gene and we have identified CYGB as a candidate tylosis with oesophageal cancer gene. Although CYGB is not mutated in tylotic individuals or in a series of sporadic squamous cell oesophageal carcinomas, we have shown that its expression is strongly downregulated in non-cancerous oesophageal biopsies from patients with TOC compared with Gambogic-acid normal biopsies. CYGB is also methylated and downregulated in sporadic oesophageal, lung and head and neck cancers. Recently, downregulation of cytoglobin has also been shown to promote chemically induced carcinogenesis in rodent liver. There is compelling evidence that oxidative damage to DNA, if not repaired, contributes to the formation of mutations that are known to be important in the aetiology of human carcinogenesis. We therefore hypothesise that loss of cytoglobin expression would render oesophageal cells more susceptible to the damaging effects of ROS, and that this contributes to the observed phenotype of TOC. In the current study we tested this hypothesis by manipulating cytoglobin expression in both normal oesophageal epithelial cells and oesophageal squamous cell carcinoma cells, which have normal physiological and no endogenous expression of cytoglobin, respectively. Previous work in our and other laboratories has shown that cytoglobin has the potential to detoxify reactive oxygen species in vitro when overexpressed in various cell culture systems. Furthermore, downregulation of cytoglobin byRNAi has also recently been shown to sensitise glioma cells to oxidative stress, induced by both inhibition of the electron transport chain with antimycin A, and ionizing radiation. Further support for a role for cytoglobin in detoxification of ROS is the biochemical.