Primary liver cancer is the most common malignant tumor in human with high mortality. However, the exact molecular mechanism of liver carcinogenesis is not completely defined and little is known about its prevention. On the basis of published data from our laboratory and exciting new preliminary findings, we hypothesize that cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), the two most important rate-limiting key enzymes in the control of prostaglandin synthesis, importantly contribute to liver carcinogenesis through EP1 receptor-mediated activation of Akt. Therefore, interruption of the prostaglandin-associated signaling pathways may provide promising potential therapeutic targets for the chemoprevention and treatment of human liver cancer. This application proposes three specific aims to evaluate the above hypotheses.
Aim I will examine the hypothesis that the cPLA2 and COX-2-mediated prostaglandin signaling pathways promote liver cancer development by utilizing animal models of hepatocarcinogenesis. Mice with disruption or targeted overexpression of cPLA2 and COX-2 in liver will be utilized to examine the spontaneous or hepatic carcinogen-induced liver cancer development.
Aim II will evaluate the effect of overexpression or antisense/siRNA depletion of cPLA2 and COX-2 on liver cancer growth, in vitro and in SCID mice.
Aim III is proposed to evaluate the hypothesis that activation of Akt by EP1 receptor is a key signaling pathway that mediates the cPLA2 and COX-2- induced liver cancer growth. The proposed studies will help understand the pathobiological functions and molecular mechanisms of cPLA2 and COX-2-controlled prostaglandin metabolism in liver cancer promotion and progression. The results will provide important therapeutic implications for the chemoprevention and treatment of human liver cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA106280-01A1
Application #
6865156
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Yassin, Rihab R,
Project Start
2005-01-01
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$237,088
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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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