| Summary: | 博士 === 國立臺灣大學 === 分子醫學研究所 === 100 === Prostaglandin reductase 2 (PTGR2) is an enzyme that catalyses the NADPH- dependent reduction of 15-keto-PGE2 into the downstream metabolite 13,14-dihydro- 15-keto-PGE2. Previously, 15-keto-PGE2 was demonstrated to act as a natural ligand for peroxisome proliferator-activated receptor γ (PPARγ), which plays a distinct role in mediating differentiation of adipocytes and regulating lipid metabolism. The suppressive effect of PTGR2 on PPARγ activity and adipocyte differentiation were characterized. However, there is still very little knowledge on the biological role of PTGR2. It is well established that different prostanoids & their synthases play an important role in gastric cancer. Many of these prostaglandin metabolites also serve as natural ligands for PPARγ. Thus, whether PTGR2 plays a distinct role in cancer biology is of interest.
In this thesis, functional and mechanistic analyses on the impact of PTGR2 in gastric cancer are presented. Downregulation or overexpression of PTGR2 was performed by lentiviral technology in AGS and SNU-16 gastric cancer cell lines. In contrast to overexpressing PTGR2, in vitro analysis showed that PTGR2 knockdown resulted in decreased proliferation rate and colony formation, and in vivo xenograft models showed slower growth of tumors. Mechanistically, PTGR2 knockdown induced cell death, altered mitochondrial function, and produced higher reactive oxygen species (ROS), which lead to the activation of ERK1/2 and caspase 3, with increased Bcl-2 and suppressed Bax expressions. Furthermore, treatment of AGS cells with synthetic PTGR2 inhibitors as well as lyophilized lipids reconstituted with 13,14-dihydro-15- keto-PGE2 showed the dependency of PTGR2 on its catalytic activity in its oncogenic potency. To investigate additional oncogenic pathways and molecules in which PTGR2 act on, microarray was also performed and identified potential role of PTGR2 in cancer cell migration. Lastly, clinical immunopathological staining showed strong PTGR2 expression in the gastric tumor portion relative to nearby non-tumor areas, and its expression negatively correlated with the survival of patients with intestinal type gastric cancer. Furthermore, PTGR2-knockdown cells were more sensitive to cisplatin and 5-fluorouracil. Taken together, our findings not only provide functional and mechanistic evidence of the involvement of PTGR2 in gastric cancer, but also clinical observations affirm the significance of PTGR2 in gastric cancer and suggest PTGR2-target based therapy is worth further evaluation.
|
|---|
