Nox1 Oxidant Stress, Ras And Colon Cancer'The NADPH-oxidase Nox1 generates reactive oxygen species (ROS) that function through signalingpathways to activate mitogenic growth and angiogenesis. Nox1 is overexpressed in -60-70% of early humancolon cancers, consistent with a role in tumorigenesis. Based on cell model studies, we hypothesize thatNox1 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 Nox1overexpression is linked to oncogenic mutations in K-Ras and/or to inactivating mutations in the tumorsuppressors p53 and ARC. The extent to which Nox1 overexpression in tumors is associated with NFkappaBactivation, 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 oncogenicmutation, Nox1 overexpression, and intestinal cancer, we previously developed Nox1-overexpressing andNox1 -knockout mice. By crossing villin K-RasV12 mice with Nox1-knockout and Nox1-overexpressinganimals, we will test whether Nox1 mediates V12-Ras-directed tumorigenesis. By investigating Nox1expression, mutation of tumor suppressors (p53 and ARC) and activation of growth-associated signalingpathways (Akt/PKB, ERK1,2, JNK) in tumors and adjacent normal tissue, we will determine molecular eventsrelevant to tumor initiation and progression. The mechanisms by which Nox1 regulates mitogenic growth willbe further investigated by evaluating activation of NF-kappaB and the induction/activation of Cox2. We willevaluate collaboratively with other projects the role of Nox1 in the induction of the DNA damage response inthe tumor initiation/progression pathway. We will also investigate the hypothesis that Nox1-derived ROSstimulates mitogenic growth by inhibiting protein tyrosine phosphatases, leading to a increased tyrosinephosphorylation levels of important mitogenic regulatory proteins. These studies will provide novelinformation regarding the role of Nox1 in gastrointestinal cancers, its relationship to oncogenic mutations inK-Ras, and the mitogenic signaling systems utilized by Ras and Nox1.
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