? ? Peroxisome proliferator-activated receptor-gamma (PPAR?) is a potent suppressor of early stage colon carcinogenesis, and therefore a particularly attractive target for colon cancer chemoprevention. A number of studies have shown that activation of PPAR? in colon cancer cells inhibits proliferation and induces differentiation, suggesting that the tumor-suppressive effects of PPAR? are due to the ability to revert the transformation of early stage colon cancer cells. However, the mechanism that accounts for this process is unknown. We have recently completed a genomic profile of a battery of PPAR? sensitive and resistant human colon cancer cell lines. Our data reveal that reversion of the transformed phenotype is associated with inhibition of micro RNA (miR) metabolism. Specifically, PPAR? inhibits expression of Dicer1, which catalyzes the rate limiting step in conversion of inactive 75nt pre-miRs to active 21-23nt miRs. Downregulation of Dicer1 by PPAR? is associated with inhibition of maturation of a known oncogenic micro RNA, mir21. Recent data indicate that maintenance of the transformed phenotype may depend upon expression of colon cancer specific miRs (so-called oncomirs). Our observation that PPAR? inhibits Dicer1 expression suggests that the tumor suppressive effects of PPAR? may result from inhibition of oncomir-dependent processes that are required for maintenance of the transformed phenotype. To test this hypothesis, we will determine if knockdown of Dicer1 inhibits transformation in early stage colon cancer cells. We determine if overexpression of Dicer1 blocks the tumor suppressive effects of PPAR?, and we will test the hypothesis that some subset of PPAR? target genes are regulated secondary to repression of Dicer1 and inhibition of miR metabolism. Elucidation of this novel mechanism will provide fundamental new insight into our understanding of how PPAR? suppresses tumor formation, how miR metabolism is regulated in the colon, and how specific oncomirs contribute to transformation of colonic epithelial cells. Furthermore, we will identify a cohort of PPAR?/Dicer1 target mRNAs and miRs that may be essential for maintenance of the transformed state and therefore potential new targets for colon cancer chemoprevention. ? ? ?
| Su, Weidong; Bush, Craig R; Necela, Brian M et al. (2007) Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. Physiol Genomics 30:342-53 |
| Bush, Craig R; Havens, Jennifer M; Necela, Brian M et al. (2007) Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor gamma and calcium signaling in human colorectal cancer cells. J Biol Chem 282:23387-401 |
