AbstractsBiology & Animal Science


by Min Yan

Institution: Case Western Reserve University
Department: Molecular Biology and Microbiology
Degree: PhD
Year: 2005
Keywords: Health Sciences, Oncology; PGDH; TGF-¿¿¿¿; Colon; Colon Cancer; PGDH Expression; Induction Of PGDH; CANCER
Record ID: 1761431
Full text PDF: http://rave.ohiolink.edu/etdc/view?acc_num=case1100464322


Cyclooxygenase-2 (COX2), the enzyme catalyzing the key step in prostaglandin synthesis, is over-expressed in 85% of colon cancers. The prostaglandin products of COX2, e.g. PGE2, have been implicated in regulating proliferation, migration and angiogenic properties of tumor cells. 15-hydroxyprostaglandin dehydrogenase (PGDH) is the key enzyme responsible for prostaglandin inactivation by converting the 15-hydroxyl group to a 15-keto group. In contrast to numerous studies on COX2 and its prostaglandin products, relatively little is known about the role of PGDH in tumorigenesis. We have found that PGDH expression is markedly reduced in most colon cancer samples compared to normal colon at both RNA and protein level. Reconstitution of functional PGDH expression to physiological level in colon cancer cells markedly suppresses their capacity to form tumors in athymic mice. These data indicate PGDH has a role in suppressing colon cancer, and that PGDH loss in colon cancer may functionally promote tumor growth. Meanwhile, mutant PGDH with little enzyme activity does not confer growth inhibition on colon cancer cells in vivo. In addition, we have found TGF-beta directly induces PGDH expression in multiple colon cell lines, suggesting that PGDH induction is recruited as one effector of TGF-beta mediated suppression of colon tumorigenesis. This is the first unequivocal connection between TGF-beta and prostaglandin pathway in human colonocytes. Indeed, PGDH expression is localized to colonocytes located on the upper reaches and luminal surface of colon crypts, where colonocytes have ceased cell division and undergone differentiation. In addition, we demonstrate that TGF-beta induction of PGDH occurs at the transcriptional level without need of new protein synthesis. We also provide evidence that PGDH induction may not be a secondary effect of TGF-beta-induced growth inhibition. Our data not only implicates PGDH as another crucial hit in the prostaglandin pathway in colon tumorigenesis besides COX2, but also provides evidence that loss of TGF-beta responsiveness accounts for reduction of PGDH expression in colon cancer.