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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Salnikow, Konstantin
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Tulane University
Schools of Medicine
New Orleans
United States
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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
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) Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1. Am J Pathol 185:1033-44
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
Yao, Lu; Han, Chang; Song, Kyoungsub et al. (2015) Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer Res 75:1388-98
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
Lu, Lu; Byrnes, Kathleen; Han, Chang et al. (2014) miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 12:890-900
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

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