Primary liver cancer is the common malignant neoplasm in human with high mortality. The tumor usually develops in the presence of continuous hepatic inflammation and epithelial regeneration in the setting of chronic inflammatory liver diseases. Recent studies from our laboratory have shown an important role of the cytosolic phospholipase A21 (cPLA21) and cyclooxygenase-2 (COX-2)-controlled prostaglandin signaling cascade in liver carcinogenesis. Therefore, inhibiting prostaglandin pathway may represent an effective therapeutic approach to disrupt the inflammation, dysplasia and malignant transformation processes. However, the effort for utilizing pharmacological COX-2 inhibitors for liver cancer chemoprevention and treatment in patients has been hindered by the potential cardiovascular side effect associated with long-term use of some COX-2 inhibitors. Thus, there is an urgent and practical need to identify novel and safer therapeutic targets downstream of COX-2, such as those inhibiting prostaglandin E2 (PGE2) signaling, for effective chemoprevention with lesser side effect. In this continuation application, we hypothesize that the interaction between the prostaglandin receptor, EP1, and EGFR/2-catenin is crucial for hepatocarcinogenesis and that simultaneous inhibition of these key molecules may synergistically prevent hepatocarcinogenesis and provide effective anti-tumor therapy. This hypothesis will be evaluated in three specific aims by utilizing complementary approaches of cultured liver cancer cells and animal models of hepatocarcinogenesis.
Aim 1 is designed to delineate the interplays between prostaglandin and EGFR/2-catenin signaling pathways in cultured liver cancer cells and in hepatocellular cancer tissues from the cPLA21 and COX-2 transgenic and knockout mice.
In Aim 2, mice with overexpression of COX-2 or cPLA21 plus deletion of EGFR or 2-catenin in the liver will be developed to determine hepatic carcinogen-induced tumor development, with the expectation that deletion of EGFR/2- catenin will prevent COX-2 or cPLA21-induced hepatocarcinogenesis.
Aim 3 is designed to evaluate the hypothesis that blocking the prostaglandin receptor EP1 with concomitant inhibition of EGFR or 2-catenin may represent an effective and safe therapeutic strategy for the chemoprevention and treatment of liver cancer. The proposed studies are expected to provide important therapeutic implications for the chemoprevention and treatment of human liver cancer.

Public Health Relevance

The current continuation proposal will delineate the interplays between prostaglandin and EGFR/2-catenin signaling pathways in liver cancer cells and in animal models of hepatocarcinogenesis. The effect of simultaneous inhibition of the prostaglandin receptor EP1 and EGFR/2-catenin on liver tumor growth will be examined in vitro and in animal models of hepatocarcinogenesis. The proposed studies will define the molecular mechanisms responsible for liver cancer growth and provide important therapeutic implications for future effective chemoprevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106280-08
Application #
8318555
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Salnikow, Konstantin
Project Start
2004-04-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$238,311
Indirect Cost
$79,981
Name
Tulane University
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Qadir, Ximena V; Han, Chang; Lu, Dongdong et al. (2014) miR-185 inhibits hepatocellular carcinoma growth by targeting the DNMT1/PTEN/Akt pathway. Am J Pathol 184:2355-64
Lu, D; Han, C; Wu, T (2014) 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPAR?-mediated activation of p21WAF1/Cip1. Oncogene 33:1101-12
Lu, Lu; Byrnes, Kathleen; Han, Chang et al. (2014) miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 12:890-900
Zhu, Hanqing; Han, Chang; Lu, Dongdong et al. (2014) miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator. Am J Pathol 184:2828-39
Wang, Ying; Han, Chang; Lu, Lu et al. (2013) Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58:995-1010
Lu, Dongdong; Han, Chang; Wu, Tong (2013) 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator-activated receptor-ýý, SMAD2/3, and TAP63 proteins. J Biol Chem 288:19484-502
Song, Kyoungsub; Han, Chang; Zhang, Jinqiang et al. (2013) Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology 58:1681-92
Zhang, Jinqiang; Han, Chang; Zhu, Hanqing et al. (2013) miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF). Am J Pathol 182:1629-39
Zhang, Jinqiang; Han, Chang; Wu, Tong (2012) MicroRNA-26a promotes cholangiocarcinoma growth by activating ?-catenin. Gastroenterology 143:246-56.e8
Li, Guiying; Chen, Weina; Han, Chang et al. (2011) Cytosolic phospholipase A(2)* protects against Fas- but not LPS-induced liver injury. J Hepatol 55:1281-90

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