PPARs in intestinal and colonic tumorigenesis

Institution:	Salk Institute for Biological Studies
Investigator(s):	Yongxu Wang, Ph.D.
Award Cycle:	2001 (Cycle 10)	Grant #: 10FT-0033	Award: $74,952
Subject Area:	Cancer
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

Colorectal cancer is the second leading cause of death from cancer in the United States. Recent studies have clearly shown that cigarette smoking, especially long term continuous smoking, can significantly increases the risk of colorectal cancer death in both men and women. The carcinogens in tobacco smoke are thought to damage genes in intestinal cells, which in turn lead to colorectal cancer. However, how exactly smoke does this is completely unknown; this is largely due to our insufficient knowledge of which genes are important for colorectal cancer. A group of proteins named PPARs have recently been implicated in this disease. When they bind to some small molecules called ligands, PPARs become activated and can perform their functions. These ligands include dietary fatty acids, anti-inflammatory drugs and anti-diabetic drugs. PPARs consist of three subtypes: PPARa, PPARg, and PPARd. Ligand-bound PPARg proteins have been found to enhance intestinal tumorigenesis in mice predisposed to intestinal tumors, while the same molecules inhibit the growth of human colon cancer cells. A possible role of PPARd in colorectal cancer has also been suggested by recent studies. In human colorectal cancer tissues, the level of PPARd increases. Moreover, PPARd expression is controlled by the protein named APC, a tumor suppressor that prevents colorectal cancer. However, definitive evidence concerning whether and how PPARg and PPARd participate in colorectal cancer is missing. In this proposal we will generate animal models that exhibit active forms of PPARg and PPARd in intestines to directly examine the in vivo function of PPARs in colorectal cancer. We will examine: (1) How PPARg or PPARd affects intestinal development; (2) Whether the active form of PPARg or PPARd is sufficient to cause colorectal cancer; (3) How PPARg or PPARd affects cancer growth and/or progression in animal models of colorectal cancer; (4) What are the downstream genes regulated by PPARs in colorectal cancer. The results of this study will not only open a new direction to explore the mechanism of how smoke can cause colorectal cancer but also help to develop specific and effective ligands for treatment of this disease.

Publications

Peroxisome-proliferator-activated receptor delta activates fat mtabolism to prevent obesity.
Periodical: Cell			Index Medicus:
Authors: Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM				ART
Yr: 2003	Vol: 113	Nbr:	Abs:	Pg: 159-170

Peroxisome-proliferator-activated receptor delta activates fat mtabolism to prevent obesity.
Periodical: Cell			Index Medicus:
Authors: Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM				ART
Yr: 2003	Vol: 113	Nbr:	Abs:	Pg: 159-170