Abstract
摘要:前列腺素還原酶(PTGR2) 是一種可將15-keto-PGE2 代謝成為13,14-dihydro-15-keto-PGE2 的酵素。在我們之前已發表的研究中發現15-keto-PGE2 是PTGR2 的受質, 且也是PPARγ 的天然配體, 而PPARγ本身受配體調控而可影響脂肪細胞分化與脂肪代謝。目前除已知PTGR2 可抑制PPARγ活性與脂肪細胞分化外, 對PTGR2 的生化功能了解極為有限。許多研究證實前列腺素與其相關合成酵素和腫瘤的發育與轉移有關。而前列腺素與其代謝產物也是PPARγ 的配體。經由其交互作用可知前列腺素和PPARγ 皆在腫瘤形成與轉移扮演一定角色。因此我們質疑是否PTGR2 也與癌症有關。在我們初步研究發現PTGR2 與其代謝產物13,14-dihydro-15-keto-PGE2 在胃癌檢體中有顯著性表現且其和病人存活率也有相關性。而在PTGR2 剃除之胃癌細胞株(AGS 與SNU-16) 中也發現其貼附性與非貼附性細胞生長皆受到抑制。基於以上的初步結果我們假設PTGR2 對胃癌病變有重要角色, 所以本計畫探討的主題將包含1. 胃癌細胞中與PTGR2 相關基因表現的研究2. 剔除PTGR2 與過量表現PTGR2 之胃癌細胞株的癌化特性表現差異研究3. PTGR2 影響胃癌癌化特性是否經由PPARγ 或其他訊息途徑4. 以動物實驗模式証實PTGR2 可影響胃癌細胞生長與轉移5. PTGR2 siRNA 於胃癌生長與轉移治療上的應用6. PTGR2 抑制劑在胃癌治療上的應用與發展性研究經由完成以上研究, 我們期望能對PTGR2 在胃癌角色扮演有一定了解, 並可進一步釐清代謝症狀與癌症之間的關聯性。
Abstract: Prostaglandin reductase 2 (PTGR2) is an enzyme that catalyses the NADPH-dependentreduction of 15-keto-PGE2 into the downstream metabolite 13,14-dihydro-15-keto-PGE2. Inour previous publication, we found that 15-keto-PGE2 is a specific substrate of PTGR2, and italso acts as a natural ligand for peroxisome proliferator-activated receptor γ(PPARγ). PPARγis a ligand-activated nuclear receptor that plays a distinct role in mediating differentiation ofadipocytes and regulating lipid metabolism. The suppressive effect of PTGR2 on PPARγactivity and adipocyte differentiation were characterized. However, there is still very littleknowledge on the biological role of PTGR2.It is well established that different prostanoids & their synthases are known to playdistinct roles in tumor progression and cancer metastasis. Later studies have also shown thatmany prostaglandin metabolites serve as natural ligands for PPARγ, and thus the impact ofseveral prostaglandins on cancer progression is dependent on their binding to and theactivation of PPARγ. Thus, the PPARγpathway is one of the routes in which prostaglandinsact on to modulate cancer metastasis.Given the important role of prostaglandins and PPARγ activity in cancer progression,we wondered if PTGR2 plays a distinct role in cancer biology. Our preliminary clinical datashowed that PTGR2 and its enzymatic product 13,14-dihydro-15keto-PGE2 were specificallyhighly expressed in gastric cancer tumor sections, and their expressions also correlate withpatients’ survival. Knockdown PTGR2 in gastric cancer cell lines (AGS and SNU-16) alsoshowed decreased anchorage-dependent and independent growth. Based on our findings thusfar, we hypothesized that PTGR2 is a promising candidate with distinct impact on gastriccarcinogenesis. In this proposal, we attempt to study the followings:1. PTGR2-dependent gene expression profiles in gastric cancer2. Cancer cell biology of PTGR2 silencing/overexpression in gastric cancer cell lines3. Whether the impact of PTGR2 on gastric carcinogenesis is mechanistically linked to themodulation of PPARγ activity or other processes4. Prove the importance of PTGR2 on gastric tumor growth and metastasis through animalmodel5. Proof of concept trial of siRNA on gastric cancer growth/metastasis6. Compounds development for gastric cancer therapyBy answering the specific aims listed, we hope that through this proposal themechanisms and the importance of PTGR2 in gastric cancer biology will be clearly elucidated.Further understanding of the linkage between metabolic syndrome and cancer metastasismight also be uncovered.
Keyword(s)
胃癌
前列腺素
過氧化氫受體γ
前列腺素還原酶PTGR2
轉移
gastric cancer
prostaglandins
PPARγ
PTGR2
metastasis