Author: Xiaohan Wang

Publisher:

Published: 2019

Total Pages:

ISBN-13:

Peroxisome proliferator-activated receptor / (PPAR/) is an important regulator in various physiological processes, including lipid metabolism and glucose homeostasis. However, its role in cancer remains controversial. Although PPAR/ is highly expressed in the intestines of normal adults, it has been reported to be up- or down-regulated during colon tumorigenesis. Researchers have not reached a consensus for whether PPAR/ is beneficial, detrimental, or unrelated to colon cancer initiation, survival, growth, and metastasis, in mouse or and human cancer models.One of the first mechanisms described that PPAR/ promotes carcinogenesis was the hypothesis that PPAR/ is a target gene of the oncogenic APC/-CATENIN pathway, a major pathway that is activated by mutations in colon cancer. However, subsequent studies did not observe a correlation between PPAR/ expression and -CATENIN activation, and questioned whether PPARD (gene coding for PPAR/) is a bona fide APC/-CATENIN target protein. Moreover, the functionality of PPAR/ as influenced by the APC/-CATENIN pathway, has not been critically examined to date. Therefore, in the first part of this thesis, the hypothesis that PPAR/ is functionally regulated by the APC/-CATENIN pathway as a tumor-promoting protein was tested. We first investigated whether mutations of the APC/CTNNB1 (-CATENIN) genes or overexpression of functional -CATENIN modulate PPAR/ cellular retention and its response to ligand activation in human colon cancer cell lines. We further examined the effect of ligand activation of PPAR/ using a classic agonist, as well as selective repression of PPAR/ using ligands that stimulate its transcriptional repression activity, on the growth of colon cancer cells with wild-type or mutant APC/CTNNB1. We observed that cytosol and nuclear retention of PPAR/, with or without ligand activation, were not different between cell lines with wild-type or mutant APC/CTNNB1 (gene coding for -CATENIN). Second, target gene activation of PPAR/ following ligand activation occurred faster in cell lines with mutant APC/CTNNB1 compared to a non-mutant cell line, although this difference was not observed with transient overexpression of -CATENIN. Third, ligand activation and selective repression of PPAR/ inhibited growth in several APC/CTNNB1 mutant cell lines but had no effect on the non-mutant cell line. These results suggest that cellular retention and transcriptional activity of PPAR/ are not directly regulated by the APC/-CATENIN pathway. However, the results also suggest that PPAR/ may be enhanced by the presence of APC/CTNNB1 mutations in human colon cancer cell lines.The role of PPAR/ in colon cancer invasion and metastasis also remains elusive. In the second part of this thesis, the influence of PPAR/ activation on malignancy-related features of colon cancer was examined. We hypothesized that ligand activation or selective repression of PPAR/ would inhibit anchorage-independent growth, migration, invasion, epithelial to mesenchymal transition (EMT), and metalloprotease (MMP) activity. Results, some preliminary in nature, showed that selective repression of PPAR/ reduced anchorage-independent growth by inducing apoptosis, inhibited migration, and reduced EMT marker expression, but did not change TNF/TGF-induced MMP activity. By contrast, ligand activation of PPAR/ reduced migration and TNF/TGF-induced MMP activity, but did not affect anchorage-independent growth and EMT marker expression. These results suggest that both ligand activation and selective repression of PPAR/ reduce the malignant potential of colon cancer, although the underlying mechanisms could be different. Combined, results from this study indicate that PPAR/ is not functionally regulated by the APC/-CATENIN pathway. Further, ligand activation or selective repression of PPAR/ using synthetic ligands may modulate colon cancer growth and malignancy-related features, in particular in cells with APC/CTNNB1 mutations.