15-PGDH in Cholangiocarcinogenesis

15-PGDH 在胆管癌发生中的作用

基本信息

批准号：
9208117
负责人：
Tong Wu
金额：
$ 34.43万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208117
关键词：
Adverse effects Biliary Biliary Tract Cancer Biological Biological Process Cardiovascular system Cells Chemoprevention Cholangiocarcinoma Chronic Clonorchiasis Combined Modality Therapy Data Development Diagnosis Dinoprostone Disease Dysplasia Early Diagnosis Enzymes Epithelial Cell Proliferation Event Excision Future Genetic Transcription Goals Growth Hepatitis C Hepatobiliary Histone Deacetylase In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Injury Intrahepatic Cholangiocarcinoma Link Liver Cirrhosis Malignant - descriptor Malignant Neoplasms MicroRNAs Molecular Oncogenic Operative Surgical Procedures Oxidoreductase PPAR gamma PTGS2 gene Pathway interactions Patient risk Patients Pharmacology Play Prevention Process Prostaglandins Publishing Role Secondary to Series Survival Rate Therapeutic Intervention Tumor Suppressor Proteins Tumorigenicity Virus Diseases Xenograft Model advanced disease bile duct carcinogenicity cell growth chemotherapy cholangiocyte experimental study high risk inhibitor/antagonist mortality mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics outcome forecast prevent primary sclerosing cholangitis public health relevance tumor tumor xenograft tumorigenic

项目摘要

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.

描述（通过应用提供）：胆管癌（CCA）是一种高度恶性的胆道癌，预后不良。与胆管慢性感染与胆管癌发生之间的密切关联，我们的实验室和其他研究表明，炎症介质（例如前列腺素（PGS））在胆管癌发生中起着重要作用。在我们发表的研究和新的初步数据的基础上，我们假设15-羟基丙烷蛋白脱氢酶（15-PGDH）是一种关键酶，可以通过将亲核PGE2转化为tumor抑制肿瘤抑制15-酮-PGE2来抑制CCA的发育和进展。我们假设15-PGDH表达的诱导或重新激活可能代表了一种有希望的治疗干预措施，用于未来预防和治疗胆管癌。这些假设将使用体外研究，肿瘤异种移植模型和CCA诱导小鼠模型的完整方法进行研究。我们将评估15-PGDH对胆管癌的新小鼠模型中CCA发育的影响。我们将进一步剖析抑制CCA细胞中15-PGDH表达的机制。将进行实验，以评估组蛋白脱乙酰基酶（HDAC）通过转录抑制和microRNA-21（miR-21）通过转录后抑制在CCA细胞中沉默15-PGDH的假设。因此，我们提出了实验，以检查抑制HDAC和MIR-21的假设将诱导或重新激活15-PGDH的表达并防止CCA生长。最后，我们将进行研究，以评估15-PGDH诱导可以感觉到标准CCA化学疗法的抗肿瘤效率的假设。当前应用的总体目的是剖析胆管癌发生中15-PGDH的生物学功能和分子机制，并通过靶向这种关键的肿瘤抑制剂来探索新的治疗选择。