15-PGDH in Cholangiocarcinogenesis

 描述(申请人提供)：胆管细胞癌(CCA)是一种高度恶性的胆道癌，预后不良。我们实验室和其他实验室的研究表明，炎症介质，如前列腺素(PGs)，在胆管癌变过程中发挥着重要作用，这与胆管慢性炎症和胆管癌变之间的密切联系是一致的。根据我们已发表的研究和新的初步数据，我们假设15-羟基前列腺素脱氢酶(15-PGDH)是一种关键酶，通过将致癌前PGE2转化为抑癌的15-酮-PGE2来抑制CCA的发生和发展。我们推测，诱导或重新激活15-PGDH的表达可能是未来预防和治疗胆管癌的一种有前途的治疗干预措施。这些假说将使用体外研究、肿瘤异种移植模型和CCA诱导的小鼠模型的互补方法来检验。我们将在新的小鼠胆管癌变模型中评估15-PGDH对CCA发展的影响。我们将进一步剖析在CCA细胞中抑制15-PGDH表达的机制。实验将评估这一假设，即15-PGDH通过转录抑制被组蛋白脱乙酰酶(HDAC)和microRNA-21(miR-21)通过转录后抑制而在CCA细胞中沉默。因此，我们建议通过实验来验证这样的假设，即抑制HDAC和miR-21将诱导或重新激活15-PGDH的表达，并阻止CCA的生长。最后，我们将进行研究来评估15-PGDH诱导可以增敏标准CCA化疗的抗肿瘤疗效的假说。目前应用的总体目标是剖析15-PGDH在胆管癌变中的生物学功能和分子机制，并通过靶向这一关键的肿瘤抑制因子来探索新的治疗方案。

 DESCRIPTION (provided by applicant): Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with poor prognosis. Consistent with the strong association between bile duct chronic inflammation and cholangiocarcinogenesis, studies from our lab and others have shown that mediators of inflammation, such as prostaglandins (PGs), play an important role in cholangiocarcinogenesis. On the basis of our published studies and new preliminary data, we hypothesize that 15- hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme that suppresses CCA development and progression by converting pro-oncogenic PGE2 to tumor suppressive 15-keto-PGE2. We postulate that induction or reactivation of 15-PGDH expression may represent a promising therapeutic intervention for future prevention and treatment of cholangiocarcinoma. These hypotheses will be examined using complementary approaches of in vitro studies, tumor xenograft models, and mouse models of CCA induction. We will evaluate the impact of 15-PGDH on CCA development in novel mouse models of cholangiocarcinogenesis. We will further dissect the mechanisms that suppress 15-PGDH expression in CCA cells. Experiments will be carried out to evaluate the hypothesis that 15-PGDH is silenced in CCA cells by histone deacetylase (HDAC) via transcriptional suppression and by microRNA-21 (miR-21) via post- transcriptional inhibition. Consequently, we propose experiments to examine the hypothesis that inhibition of HDAC and miR-21 will induce or reactivate 15-PGDH expression and prevent CCA growth. Finally, we will perform studies to evaluate the hypothesis that 15-PGDH induction can sensitize the anti-tumor efficacy of standard CCA chemotherapy. The overall objective of the current application is to dissect the biological functions and molecular mechanisms of 15-PGDH in cholangiocarcinogenesis and to explore new therapeutic options by targeting this pivotal tumor suppressor.