Pro-inflammatory prostaglandin E2 (PGE2) is the most abundant prostaglandin found in human colorectal cancers and plays a predominant role in promoting tumor growth. In contrast to the role of PGE2 in carcinogenesis and inflammation, another of the arachidonate-based bioactive lipids, endocannabinoids, exert potential anti-tumor effects on a wide spectrum of human tumors in vitro and have proven antiinflammatory properties. Opposing effects of PGE2 and endocannabinoids on inflammation and cancer progression prompted us to hypothesize that PGE2 and endocannabinoids coordinately control tumor progression. Endocannabinoids primarily activate two G-protein-coupled cannabinoid receptors CBI and CB2 and are degraded by fatty acid amide hydrolase (FAAH). Based on our preliminary data, cross talk exists between PGE2 and endocannabinoid signaling. PGE2 can downregulate CBI expression via DNA methylation, whereas a selective COX-2 inhibitor restores CBI expression. However, little is known regarding the role of CB1, CB2 and FAAH in colorectal cancer progression. This proposal will examine the following: 1) The role of PGE2 in silencing tumor suppressors, DNA repair genes, and tumor inhibitory genes via DNA methylation during the colon tumor progression. 2) The role of endocannabinoid signaling in colorectal cancer progression by examining the biological functions of FAAH and by evaluating whether a combinational treatment of a CB1 agonist with a demethylating agent or a selective COX-2 inhibitor achieves optimal anti-tumor effects of CBI agonists in vivo. 3) The influence of endocannabinoid signaling on inflammation-associated colorectal tumorigenesis by defining the role of CB1, CB2 and FAAH in the mouse models of inflammation-associated colonic carcinogenesis and by evaluating the relative contributions of the endocannabinoid signaling in epithelial cells versus immune cells. In summary, we expect to generate novel mouse models and new approaches to study the role of PGE2-mediated inflammation, its influence on DNA methylation and suppression of the anti-inflammatory role of the endocannabinoid pathway in the progression of colorectal cancer.

Public Health Relevance

The most important aspect of both PGE2 and endocannabinoid signaling is that they have opposing effects on inflammation and carcinogenesis. PGE2 promotes inflammation and cancer progression, whereas the endocannabinoids inhibit inflammation and tumor growth. Understanding how two pathways orchestrate tumor progression will provide a significant advance in the cancer field.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077839-13
Application #
8677711
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$215,071
Indirect Cost
$24,803
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Sun, Xiaofei; Park, Craig B; Deng, Wenbo et al. (2016) Uterine inactivation of muscle segment homeobox (Msx) genes alters epithelial cell junction proteins during embryo implantation. FASEB J 30:1425-35
Wang, Dingzhi; DuBois, Raymond N (2016) The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression. Trends Mol Med 22:1-3
Hiraoka, Takehiro; Hirota, Yasushi; Saito-Fujita, Tomoko et al. (2016) STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088
Reddy, Vishruth K; Short, Sarah P; Barrett, Caitlyn W et al. (2016) BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. Stem Cells 34:1626-36
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Etemadi, Nima; Chopin, Michael; Anderton, Holly et al. (2015) TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife 4:
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Li, Mei-Hong; Swenson, Rolf; Harel, Miriam et al. (2015) Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma. J Pharmacol Exp Ther 354:261-8
Wang, Dingzhi; Fu, Lingchen; Sun, Haiyan et al. (2015) Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice. Gastroenterology 149:1884-1895.e4

Showing the most recent 10 out of 328 publications