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.

Public Health Relevance

Cholangiocarcinoma (CCA) is an aggressive cancer with high mortality. The incidence of CCA is rising worldwide and currently there is no effective chemoprevention or treatment. Early detection is often difficult and most CCAs are diagnosed as advanced diseases which preclude curative surgical resection. Currently, CCA has a dismal 5-year survival rate of less than 10% and the treatment options remain limited. Thus, there is a practical and urgent need to develop new therapeutic strategies for more effective anti-tumor therapy. The current proposal is highly significant as it focuses on a pivotal tumor suppressor in cholangiocarcinoma. The studies will lead to the development of new target and combination therapies for future prevention and treatment of this devastating malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102325-14
Application #
9850556
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Yassin, Rihab R
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
14
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tulane University
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Wang, Ying; Chen, Weina; Han, Chang et al. (2018) Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF-?B/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis. Am J Pathol 188:2605-2616
Ungerleider, Nathan; Han, Chang; Zhang, Jinqiang et al. (2017) TGF? signaling confers sorafenib resistance via induction of multiple RTKs in hepatocellular carcinoma cells. Mol Carcinog 56:1302-1311
Yao, Lu; Chen, Weina; Song, Kyoungsub et al. (2017) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury. PLoS One 12:e0176106
Kwon, Hyunjoo; Song, Kyoungsub; Han, Chang et al. (2017) Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway. Am J Pathol 187:2288-2299
Zhang, Jinqiang; Baddoo, Melody; Han, Chang et al. (2016) Gene network analysis reveals a novel 22-gene signature of carbon metabolism in hepatocellular carcinoma. Oncotarget 7:49232-49245
Yao, Lu; Chen, Weina; Han, Chang et al. (2016) Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury. Am J Physiol Gastrointest Liver Physiol 310:G1071-80
Kwon, Hyunjoo; Song, Kyoungsub; Han, Chang et al. (2016) Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease. Hepatology 63:1155-69
Chen, Weina; Han, Chang; Zhang, Jinqiang et al. (2015) miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT. PLoS One 10:e0132734
Zhu, Hanqing; Han, Chang; Wu, Tong (2015) MiR-17-92 cluster promotes hepatocarcinogenesis. Carcinogenesis 36:1213-22

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