Nox1 Oxidant Stress, Ras And Colon Cancer"""""""" The NADPH-oxidase Nox1 generates reactive oxygen species (ROS) that function through signaling pathways to activate mitogenic growth and angiogenesis. Nox1 is overexpressed in -60-70% of early human colon cancers, consistent with a role in tumorigenesis. Based on cell model studies, we hypothesize that Nox1 overexpression in human colon cancers can result from induction of Nox1 transcription by activated KRas. Human intestinal tumors vs. control tissue will be characterized to establish whether Nox1 overexpression is linked to oncogenic mutations in K-Ras and/or to inactivating mutations in the tumor suppressors p53 and ARC. The extent to which Nox1 overexpression in tumors is associated with NFkappaB activation, Cox2 overexpression and activation of growth-related signaling pathways (MARK, PI 3- kinase) will also be evaluated. To evaluate directly the causal relationships among K-Ras oncogenic mutation, Nox1 overexpression, and intestinal cancer, we previously developed Nox1-overexpressing and Nox1 -knockout mice. By crossing villin K-RasV12 mice with Nox1-knockout and Nox1-overexpressing animals, we will test whether Nox1 mediates V12-Ras-directed tumorigenesis. By investigating Nox1 expression, mutation of tumor suppressors (p53 and ARC) and activation of growth-associated signaling pathways (Akt/PKB, ERK1,2, JNK) in tumors and adjacent normal tissue, we will determine molecular events relevant to tumor initiation and progression. The mechanisms by which Nox1 regulates mitogenic growth will be further investigated by evaluating activation of NF-kappaB and the induction/activation of Cox2. We will evaluate collaboratively with other projects the role of Nox1 in the induction of the DNA damage response in the tumor initiation/progression pathway. We will also investigate the hypothesis that Nox1-derived ROS stimulates mitogenic growth by inhibiting protein tyrosine phosphatases, leading to a increased tyrosine phosphorylation levels of important mitogenic regulatory proteins. These studies will provide novel information regarding the role of Nox1 in gastrointestinal cancers, its relationship to oncogenic mutations in K-Ras, and the mitogenic signaling systems utilized by Ras and Nox1.
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