Evidence that ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits TNFα-induced epithelial-to-mesenchymal transition by modulation of SNAIL expression and stemness in human colon cancer cells

Open Access
Consevage, Kevin William
Area of Honors:
Biochemistry and Molecular Biology
Bachelor of Science
Document Type:
Thesis Supervisors:
  • Jeffrey Maurice Peters, Thesis Supervisor
  • Wendy Hanna Rose, Honors Advisor
  • peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)
Colorectal cancer patients with relatively higher expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in their primary tumors as compared to patients with relatively lower PPARβ/δ expression exhibit lower propensity of metastasis and significantly increased survival. One of the mechanisms underlying cancer metastasis is the process of epithelial-to-mesenchymal transition (EMT). This study tested the hypothesis that ligand activation of PPARβ/δ would inhibit EMT using a human colon carcinoma cell line (HCT116). EMT was induced in HCT116 cells by treating with tumor necrosis factor α (TNFα), and the influence of PPARβ/δ was determined by examining the effect of the highly specific PPARβ/δ agonist, GW0742, and/or antagonist, GSK3787. TNFα induced EMT in HCT116 cells at 36 hours as evidenced by the development of a mesenchymal-like morphology, a decrease in E-CADHERIN mRNA and protein expression and an increase in N-CADHERIN protein expression compared to controls. Ligand activation of PPARβ/δ in HCT116 cells caused a decrease in TNFα-induced N-CADHERIN expression and an increase in E-CADHERIN protein expression compared to controls, but did not prevent morphological changes associated with EMT. Antagonizing PPARβ/δ did not prevent the effects of ligand activation of PPARβ/δ on EMT in HCT116 cells. Recently, EMT has been linked to the acquisition of cancer stem cell (CSC) phenotypes. Ligand activation of PPARβ/δ caused a decrease in SNAIL mRNA expression as well as NANOG and OCT4 protein expression in HCT116 cells compared to controls. Collectively, results from this study provide evidence that ligand activation of PPARβ/δ inhibits TNFα-induced EMT in HCT116 cells by modulating stemness.