There are more than 14,000 deaths per year due to liver cancer, the most rapidly increasing type of cancer in the United States. In contrast to other cancers, liver cancer frequency and mortality is increasing. There is a distinct need for new approaches to prevent and treat this disease as the current strategies of chemotherapy and surgical treatments are not very effective. Thus, it is essential to delineate new molecular pathways involved in the etiology of liver cancer to provide new strategies with significantly better efficacy to prevent human mortality due to liver cancer. It well established that direct transcriptional up-regulation of target genes by peroxisome proliferator-activated receptor-/ (PPAR/) can modulate cellular homeostasis. However, there is also evidence that PPAR/ has epigenetic activities that include inhibiting expression of proinflammatory cytokines, chemokines and cell adhesion molecules via interacting with other transcription factors. Preliminary data demonstrates that PPAR/ can attenuate liver toxicity and pre-malignant liver tumor formation. Further, ligand activation of PPAR/ can attenuate liver toxicity by down-regulating pro- inflammatory signaling molecules. The central hypothesis of this proposal is that PPAR/ can be specifically targeted to inhibit hepatocarcinogenesis.
Aim 1 will test the hypothesis that PPAR/ attenuates tumor promotion during hepatocarcinogenesis. This will be examined by inducing liver cancer using either a chemically-induced model or an HCV-transgenic model using both wild-type and Ppar/-null mice, coupled with treatment with the high affinity PPAR/ ligand GW0742.
Aim 2 will test the hypothesis that PPAR/ attenuates tumor promotion by epigenetic modulation of inflammatory signaling in Kupffer cells. This will be examined by analysis of transgenic mice expressing a DNA binding domain mutant form of PPAR/ that can epigenetically interact with other transcription factors, but is incapable of activating PPRE-specific target genes. This analysis will also be coupled with analysis of conditional deletion of PPAR/ in Kupffer cells. Results from these innovative studies will determine if PPAR/ can be an anti-inflammatory molecular target and provide an alternative strategy for preventing and treating liver cancer. Additionally, results from these studies could lead to a significant paradigm shift in treatment strategies for liver cancer and other chronic inflammatory diseases if epigenetic modulation of inflammatory signaling mediated by PPAR/ is shown to effectively prevent hepatocarcinogenesis.

Public Health Relevance

The incidence of liver cancer is increasing as compared to other cancers whose incidence has plateaued or is decreasing. Thus, there is a need to develop new strategies to prevent liver cancer. This proposal will examine the etiology of liver cancer with an emphasis on how a nuclear receptor modulates tumor promotion. The goal of this work is to determine if this receptor represents a new target for the prevention and treatment of liver cancer, through either the direct increase in target genes that protect against liver cancer and/or through epigenetic mechanisms that modulate inflammation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140369-05
Application #
8658016
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2010-06-04
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Yao, Pei-Li; Chen, Li Ping; Dobrzański, Tomasz P et al. (2015) Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms. Oncotarget 6:36319-37
Peters, Jeffrey M; Yao, Pei-Li; Gonzalez, Frank J (2015) Targeting Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) for Cancer Chemoprevention. Curr Pharmacol Rep 1:121-128
Yao, Pei-Li; Chen, LiPing; Hess, Rex A et al. (2015) Peroxisome Proliferator-activated Receptor-D (PPARD) Coordinates Mouse Spermatogenesis by Modulating Extracellular Signal-regulated Kinase (ERK)-dependent Signaling. J Biol Chem 290:23416-31
Peters, Jeffrey M; Gonzalez, Frank J; Müller, Rolf (2015) Establishing the Role of PPARβ/δ in Carcinogenesis. Trends Endocrinol Metab 26:595-607
Zhu, Bokai; Ferry, Christina H; Markell, Lauren K et al. (2014) The nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. J Biol Chem 289:20102-19
Zhu, B; Ferry, C H; Blazanin, N et al. (2014) PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene 33:5348-59
Yao, Pei-Li; Morales, Jose L; Zhu, Bokai et al. (2014) Activation of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) inhibits human breast cancer cell line tumorigenicity. Mol Cancer Ther 13:1008-17
Yao, Pei-Li; Gonzalez, Frank J; Peters, Jeffrey M (2014) Targeting estrogen receptor-β for the prevention of nonmelanoma skin cancer. Cancer Prev Res (Phila) 7:182-5
Montanez, Jessica E; Peters, Jeffrey M; Correll, Jared B et al. (2013) Metabolomics: an essential tool to understand the function of peroxisome proliferator-activated receptor alpha. Toxicol Pathol 41:410-8
Peters, Jeffrey M; Shah, Yatrik M; Gonzalez, Frank J (2012) The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer 12:181-95

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