Role of ß-catenin and Leukotriene in Colon Cancer Progression

Abstract: Abstract Colorectal cancer is the third most common cancer worldwide. Deregulation of Wnt/β-catenin signalling pathway is an early hallmark of colon cancer. Were nuclear accumulation of β-catenin is a marker of activated canonical Wnt/β-catenin signaling. One of the risk factors for development of colon cancer is inflammatory bowel disease. Inflammatory microenvironment is an essential component of most tumors. Interestingly, high levels of the pro-inflammatory mediator leukotriene D4 (LTD4) in association with its receptor CysLT1 goes with poor prognosis for colon cancer patient. It is therefore of interest to further investigating the effect of LTD4/CysLT1R in tumor progression. The aim of my thesis was to investigate the role of β–catenin signaling in colon cancer progression and the effect of LTD4. I found that activation of CysLT1R via LTD4 increased the translocation and accumulation of β–catenin to the nucleus which induce proliferation of HCT116 colon cancer cells through phosphorylation of GSK-3β and activation of Tcf/Lef. Furthermore, LTD4 decrease both membranous E-cadherin and β–catenin which lead to an increase migration of HCT116 colon cancer. I also found that membrane expression of β–catenin is associated with good prognosis while nuclear GSK-3β is associated with poor prognosis in colon cancer patient. The combination of no membrane β–catenin and nuclear GSK-3β is associated with an overall poor survival. In addition I observed that no nuclear GSK-3β in combination with moderate membrane E-cadherin is associated with good prognosis in Duke´s B colon cancer patients. It was also found that LTD4 could induce Epithelial-Mesenchymal Transition (EMT) in SW480 colon cancer cells by i) reducing membrane E-cadherin, ii) increase levels of nuclear β–catenin, iii) increase EMT marker such as vimentin and snail which leads to increase migration of SW480 colon cancer cells. In conclusion my data suggests that LTD4 in the tumor microenvironment can induce β–catenin signaling leading to increase cell proliferation and migration of colon cancer cells. Furthermore, nuclear GSK-3β could be a potential new prognostic marker (target for treatment of) for colorectal cancer.