This dissertation, "Involvement of 5-lipoxygenase in the Promotion of Colonic Tumorigenesis by Cigarette Smoke" by Yini, Ye, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of the thesis entitled Involvement of 5-Lipoxygenase in the Promotion of Colonic Tumorigenesis by Cigarette Smoke submitted by Yi-Ni, Ye for the degree of Doctor of Philosophy at The University of Hong Kong in August 2004 Substantial evidence indicates that significant exposure to cigarette smoke is associated with an elevated risk for colorectal cancer. However, the mechanisms underling the causal relationship between cigarette smoking and colorectal cancer remain to be investigated. Several studies suggest that there is a link between 5-lipoxygenase (5-LOX) and carcinogenesis in humans and animals. Therefore, in the present study, we aim to investigate the modulating role of cigarette smoke, its active components (e.g. nicotine and NNK), and also 5-LOX in colon cancer growth. Results showed that exposure to the mainstream of unfiltered cigarette smoke enhanced the incidence of inflammation-associated colonic adenomas and 5-LOX expression in balb/c mice, accompanied with an up-regulation of angiogenic factors, i.e. MMP-2 and VEGF. 5-LOX-inhibition decreased these pathological changes and also reduced angiogenesis in the colons. Cigarette smoke extract (CSE) enhanced cell proliferation and the levels of 5-LOX, MMP-2 and VEGF in SW1116 colon cancer cells. It also promoted 5-LOX DNA de-methylation and the enzyme activity. 5-LOX-inhibition decreased the MMP-2 and VEGF expressions induced by CSE. In addition, CSE also indirectly stimulated the human umbilical vascular endothelial cell (HUVECs) proliferation, a biological activity closely related to angiogenesis during tumor growth. This was again blocked by the 5-LOX-inhibitor. In the nude mouse xenograft study, pretreating SW1116 cells with CSE promoted colon tumor growth. Inhibitors of COX-2 and 5-LOX reduced the tumor size. COX-2-inhibitor decreased the PGE level while increased the LTB level in 2 4 the xenograft. In contrast, 5-LOX-inhibitor reduced the LTB level but the PGE 4 2 level was unchanged. Combined treatment with both COX-2 and 5-LOX inhibitors further inhibited the tumor growth together with the down-regulation of PGE and LTB levels. Nicotine, the active ingredient in CSE, stimulated SW1116 cell proliferation. It enhanced EGFR and c-Src phosphorylation levels together with 5-LOX expression. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX expression. Combination of both inhibitors produced additive effect. 5-LOX inhibitor had no effect on the phosphorylation levels of EGFR and c-Src, but reduced cell proliferation. Nicotine also promoted tumor growth in vivo. This acceleration corresponded well with the increased vascularization and its pro-angiogenic factors. Inhibitors of EGFR, c-Src and 5-LOX all impeded the tumor growth induced by nicotine. NNK, a nitrosamine found in CSE, also stimulated colon cancer cell proliferation, enhanced α7-nAChR mRNA level and NF-κB DNA binding activity, as well as 5-LOX and COX-2 expressions. The specific α7-nAChR antagonist inhibited these biological events. Inhibition of 5-LOX had no effect on α7-nAChR mRNA expression, but inhibited cell proliferation and activation of NF-κB and COX-2. In addition, it was found that NF-κB played a modulating role between COX-2 and 5-LOX in the promotion of colon cancer growth. Taken together, the present study demonstrates the central role of 5-LOX and its relationship with the p