15-PGDH is a prostaglandin degrading enzyme that my laboratory, in a recent """"""""from the cover"""""""" PNAS paper, has shown is a new candidate colon cancer suppressor gene that acts as an enzymatic antagonist of the COX-2 prostaglandin synthesizing colon cancer oncogene. Our initial publication demonstrated that 15- PGDH: is highly expressed in normal human colon, is ubiquitously lost in human colon cancer, and when re- expressed by transfection blocks the ability of colon cancer cells to establish tumors in athymic mice. The goal of this proposal is to now explore the potency of 15-PGDH suppression of colon neoplasia in the in vivo setting, to elucidate the biological mechanism of 15-PGDH tumor suppression, and to determine if 15-PGDH allelic variants function to confer human colon cancer susceptibility.
The specific aims of this proposal are: i) To employ 15-PGDH knockout mouse models to determine if 15-PGDH loss confers in vivo sensitivity to intes) To determine the broad potency of 15-PGDH re-expression in blocking tumor take and in inducing regression of tumor growth in human colon cancer cell lines implanted in athymic mice, iv) To identify genes and signaling pathways that are regulated by the presence or absence of 15-PGDH in in vivo models, including in 15-PGDH knockout and transgenic mice, and including in colon cancer xenografts in which 15-PGDH expression has been re-induced. v) To assess whether 15-PGDH allelic variants contribute to determining human colon cancer susceptibility by testing for association of 15-PGDH locus SNP variants to colon neoplasia development, testing in a cohort of individuals with sporadic colon cancers versus controls, and in a cohort of affected versus unaffected individuals from kindreds demonstrating familial clustering of colon neoplasia. Colon cancer is the second leading cause of cancer death. These studies will elucidate the role of 15-PGDH in colon cancer development, in determining colon cancer risk, and as a target for colon cancer prevention. ? ? ? ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????
