|Budget Amount *help
¥11,400,000 (Direct Cost: ¥11,400,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2002: ¥6,500,000 (Direct Cost: ¥6,500,000)
Among the NADPH oxidase (Nox)/Dual oxidase (Duox) family, Nox1 is dominantly expressed in the colon among human tissues. Guinea pig gastric mucosal cells in primary culture express Nox1 and are able to release O_2^- at much higher rates when exposed to Helicobacter pylori (H. pylori) lipopolysaccharide (LPS) from type I, but not from less virulent type II strains, suggesting that Nox1 may be involved in the pathogenesis of H. pylori-associated diseases. Using this culture system, we have revealed that the H. pylori LPS-stimulated O_2^- production in gastric mucosal cells require two distinct events : transcriptional up-regulation of Nox1 and its novel organizer NOXO1, and activation of Rac1 (Am J Physiol, 2005). Normal human gastric mucosa or chronic atrophic gastritis did not express Nox1 and NOXO1, while these mRNAs and proteins were specifically co-expressed in well and poorly differentiated adenocarcinomas as well as signet-ring cell carcinomas, suggesting that Nox1 and NOXO1 may b
e associated with inflammation- and ROS-related carcinogenesis in Helicobacter pylori-infected stomach.
Primary cultures of guinea pig large intestinal epithelial cells constitutively expressed Nox1, p22^<phox>, p67^<phox>, Nox activator 1 (NOXA1), NOXO1, and Rac1, and this oxidase was in a fully activated status. Overexpression of NOXO1 in T84 cells enhanced PMA-stimulated superoxide release. Flagellin from Salmonella enteritidis further augmented the release in association with the induction of Nox1 protein (J Immunol). Nox1 protein was constitutively expressed in surface mucous cells of the normal human colon. Nox1 protein showed maturation-dependent expression in both normal colon and tumors, and its expression was not directly linked to mitogenic activities. However, NF-κB was activated in adenoma and carcinoma cells possessing abundant Nox1 protein. Nox1 may exert a cancer-promoting effect by increasing NF-κB-dependent anti-apoptotic properties (Cancer Lett, 2005).
In this project, I have introduced potential roles of Nox1 in host defense and carcinogenesis in the gastrointestinal tract. Less