15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer

Abstract

Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/– mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression. Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/– mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression. Multistep carcinogenesis unfolds as stochastic mutations and epigenetic changes accumulate within individual cells. In concert with stromal influences, those cells that develop the correct combination of mutations in tumor suppressor genes and oncogenes become fully transformed (1Sabichi A.L. Demierre M.F. Hawk E.T. Lerman C.E. Lippman S.M. Cancer Res. 2003; 63: 5649-5655PubMed Google Scholar). As an example, the dysregulation of balanced prostaglandin metabolism in vivo contributes to carcinogenesis. Numerous reports have demonstrated the increased expression of cyclooxygenase-2 (COX-2) 1The abbreviations used are: COX, cyclooxygenase; PG, prostaglandin; PGDH, PG dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; PPAR, peroxisome proliferator-activated receptor; EGF, epidermal growth factor; EGFR, EGF receptor; PGE-M, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid; MOPS, 4-morpholinepropanesulfonic acid. in a variety of human malignancies (2Subbaramaiah K. Dannenberg A.J. Trends Pharmacol. Sci. 2003; 24: 96-102Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 3DuBois R.N. Prog. Exp. Tumor Res. 2003; 37: 124-137Crossref PubMed Scopus (26) Google Scholar), and higher COX-2 expression correlates with a poor clinical outcome (4DeLong P. Tanaka T. Kruklitis R. Henry A.C. Kapoor V. Kaiser L.R. Sterman D.H. Albelda S.M. Cancer Res. 2003; 63: 7845-7852PubMed Google Scholar). Furthermore, targeted overexpression of COX-2 in mouse mammary tissue leads directly to the development of breast carcinomas in transgenic mice (5Liu H.L. Chang S.H. Narko K. Trifan O.C. Wu M.T. Smith E. Haudenschild C. Lane T.F. Hla T. J. Biol. Chem. 2001; 276: 18563-18569Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar). Elevated levels of COX-2-derived prostaglandin E2 (PGE2) are associated with resistance to programmed cell death (6Sheng H. Shao J. Morrow J. Beauchamp R.D. DuBois R.N. Cancer Res. 1998; 58: 362-366PubMed Google Scholar) as well as stimulation of cell migration, cell proliferation, and angiogenesis (7Rozic J.G. Chakraborty C. Lala P.K. Int. J. Cancer. 2001; 93: 497-506Crossref PubMed Scopus (209) Google Scholar). Although steady-state tissue levels of PGE2 depend on relative rates of biosynthesis and breakdown, virtually all reports examining the role of PGE2 in physiology and disease have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. A plausible complementary pathway yielding increased local levels of PGE2 in cancer involves reduced degradation of PGE2 by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-PGDH catalyzes the rate-limiting step of prostaglandin catabolism (8Tai H.H. Ensor C.M. Tong M. Zhou H. Yan F. Prostaglandins Other Lipid Mediat. 2002; 68–69: 483-493Crossref PubMed Scopus (265) Google Scholar). The human gene is located on chromosome 4 and encodes a 29-kDa protein that oxidizes the 15(S)-hydroxyl group of prostaglandins to yield inactive 15-keto metabolites (9Pichaud F. Delage-Mourroux R. Pidoux E. Jullienne A. Rousseau-Merck M.F. Hum. Genet. 1997; 99: 279-281Crossref PubMed Scopus (19) Google Scholar). Genetic deletion of 15-Pgdh leads to increased tissue levels of PGE2 (10Coggins K.G. Latour A. Nguyen M.S. Audoly L. Coffman T.M. Koller B.H. Nat. Med. 2002; 8: 91-92Crossref PubMed Scopus (110) Google Scholar). Although previous studies on the distribution and activity of 15-PGDH have focused primarily on parturition and uterine biology, recent data suggest that 15-PGDH plays a role in carcinogenesis (11Rao C.V. Wang C.X. Simi B. Lubet R. Kelloff G. Steele V. Reddy B.S. Cancer Res. 1997; 57: 3717-3722PubMed Google Scholar, 12Tong M. Tai H.H. Biochem. Biophys. Res. Commun. 2000; 276: 77-81Crossref PubMed Scopus (41) Google Scholar). Although 15-PGDH may promote certain androgen-sensitive prostate cancers (13Tong M. Tai H.H. Endocrinology. 2004; 145: 2141-2147Crossref PubMed Scopus (21) Google Scholar), preliminary reports on medullary thyroid and transitional bladder cancers suggest that the loss of 15-PGDH expression contributes to malignancy (14Quidville V. Segond N. Pidoux E. Cohen R. Jullienne A. Lausson S. Endocrinology. 2004; 145: 2561-2571Crossref PubMed Scopus (39) Google Scholar, 15Gee J.R. Montoya R.G. Khaled H.M. Sabichi A.L. Grossman H.B. Urol. Oncol. 2003; 21: 266-270Crossref PubMed Scopus (45) Google Scholar). These conflicting reports are intriguing, and although no mechanism has been demonstrated in vivo that explains its down-regulation, a variety of compounds that modulate the expression and activity of 15-PGDH in vitro have been reported, including the hypoglycemic thiazolidinediones (16Cho H. Tai H.H. Arch. Biochem. Biophys. 2002; 405: 247-251Crossref PubMed Scopus (34) Google Scholar) as well as NSAIDs and PPARγ agonists (17Cho H. Tai H.H. Prostaglandins Leukotrienes Essent. Fatty Acids. 2002; 67: 461-465Abstract Full Text PDF PubMed Scopus (32) Google Scholar). To more completely understand prostaglandin function in epithelial biology, our laboratory sought to identify pathways complementary to COX-2 by which PGE2 might accumulate and contribute to colorectal carcinogenesis. The present study examines the hypothesis that decreased expression of 15-PGDH correlates with colorectal tumor formation. We present data suggesting that 15-PGDH is down-regulated in malignant disease relative to normal tissue and that epidermal growth factor (EGF) and indomethacin can modulate 15-PGDH expression in colorectal carcinoma cells. We also provide functional data both in vitro and in vivo showing that 15-PGDH expression levels correlate with enzymatic activity and production of the urinary PGE2 metabolite (PGE-M). Here we report the first indication that decreased catabolism of PGE2 may regulate tumor formation in the intestine. These data are suggestive of a previously unrecognized pathway in colorectal carcinogenesis, whereby elevated PGE2 levels derive in part from reduced expression and activity of 15-PGDH. Ultimately, this novel observation may shed light on the adverse clinical outcomes of patients with high levels of tumor-derived cyclooxygenase-2. Reagents—EGF was purchased from Sigma, and indomethacin, ciglitazone, and GW9662 were purchased from Cayman Chemical (Ann Arbor, MI). Erlotinib (Tarceva™) was obtained from Genentech (San Francisco, CA). FirstChoice mouse and human Northern blots were purchased from Ambion (Austin, TX). The Cancer Profiling Array II was purchased from BD Biosciences. Antibody to Cox-2 (160107) was purchased from Cayman Chemical, and rabbit antiserum against human 15-PGDH was a kind gift from Dr. Hsin-Hsiung Tai (University of Kentucky, Lexington, KY). The Northern blot probe for Cox-2 was generously provided by Dr. Sanjoy Das (Vanderbilt University, Nashville, TN), and that for 15-Pgdh was a kind gift from Dr. Beverly Koller (University of North Carolina, Chapel Hill, NC). The Northern probe for 15-PGDH was obtained by SpeI digestion of IMAGE clone ID 3638799 from the American Type Culture Collection (Manassas, VA). Animals and Cell Culture—C57BL/6 and C57BL/6-ApcMin+/– mice were obtained from Jackson Laboratory (Bar Harbor, ME). C57BL/6-Pgdh–/– mice were a generous gift from Dr. Beverly Koller. The mice were housed and fed with standard mouse diet in the Animal Care Facility according to National Institutes of Health and institutional guidelines for laboratory animals. LS-174T, HCT-15, HCT-116, DLD-1, HT-29, CaCo-2, Colo 201, LoVo, and SW480 cells were purchased from the American Type Culture Collection, and HCA-7 cells were a generous gift from Dr. Susan Kirkland. LS-174T, HCT-15, HCT-116, HCA-7, and HT-29 cells were maintained in McCoy's 5A medium containing 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin in a 5% CO2 atmosphere. SW480, Colo 201, and DLD-1 cells were maintained in RPMI 1640 medium containing 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin in a 5% CO2 atmosphere. CaCo-2 cells were maintained in minimum essential medium, and LoVo cells were maintained in Ham's F-12K medium containing 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin in a 5% CO2 atmosphere. Northern Blotting—Total cellular RNA was isolated from cells by TRI reagent (Molecular Research Center, Cincinnati, OH) following the manufacturer's protocol. 5 μg of total RNA was fractionated with a MOPS-formaldehyde agarose gel and transferred to Hybond N1 membrane (Amersham Biosciences). Following UV cross-linking, the blots were prehybridized for 30 min at 42 °C in Hybrisol I (Intergen Company, Purchase, NY) and then hybridized using 32P-labeled cDNA in the same buffer at 42 °C, washed, and subjected to autoradiography. Western Blotting—Cells were washed with phosphate-buffered saline and lysed with radioimmune precipitation assay buffer (50 mm Tris-HCl, pH 7.4, 150 mm NaCl, 1 mm EDTA, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, and protease inhibitors from Roche Applied Science). Protein concentrations were measured using Bio-Rad reagent. Proteins were then separated on precast 4–20% SDS polyacrylamide gels (Invitrogen) and transferred to nitrocellulose membranes. Membranes were blocked in 5% milk in Tris-buffered saline, 0.1% Tween 20 and incubated with primary and at 4 The were then with and using an (Amersham Biosciences). 15-PGDH activity was by the of from to 15-PGDH and dehydrogenase as previously H.H. PubMed Scopus Google Scholar). the 5 1 1 1 100 μg of and in a of 1 of mm Tris-HCl, pH The was to for min at °C and was by the of of following 5 was by of PGE2 levels was on the that no was in the of the 15(S)-hydroxyl group of and urinary metabolite of 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic was measured in as previously D.H. Morrow Biochem. 2004; PubMed Scopus Google Scholar). in of mouse was using in a sodium in and to pH with acid. were by using a which of standard was were in of A 5 mm and by as previously D.H. Morrow Biochem. 2004; PubMed Scopus Google Scholar). colorectal tumor were obtained from with tumor matched normal was for were and in RNA and protein from tissues were as was at and data were as the was by were of 15-PGDH with in the a preliminary we examined a range of tissue to identify the expression of 15-PGDH. 15-PGDH is to in several in (8Tai H.H. Ensor C.M. Tong M. Zhou H. Yan F. Prostaglandins Other Lipid Mediat. 2002; 68–69: 483-493Crossref PubMed Scopus (265) Google Scholar), and total RNA was by Northern blot for tissues from human and mouse In we found the expression levels in the large elevated 15-PGDH was also in the the and the A and The and are to an role in prostaglandin metabolism in vivo 2004; PubMed Scopus Google Scholar), this is the first report suggesting that 15-PGDH plays a role in the intestine. These to the relative expression of 15-PGDH is in normal malignant A preliminary of matched from human that 15-PGDH was in a range of human including those of the and We to our on the role of 15-PGDH in colorectal cancer of our on prostaglandin function in of 15-PGDH in the expression and of 15-PGDH in colorectal carcinoma we the following cell HCT-15, HCT-116, HCA-7, HT-29, DLD-1, SW480, and of the colorectal carcinoma cell lines CaCo-2, Colo 201, and LoVo that LoVo cells 15-PGDH colorectal carcinoma cells of examined in this study no 15-PGDH although certain cell lines levels of 15-PGDH including and These results are with our in vivo that most colorectal carcinomas have in 15-PGDH levels of 15-PGDH expression and activity in human colorectal cancer total RNA and protein were isolated from individual human colorectal cancer tissues and matched normal of RNA and protein were for 15-PGDH normal tumor tissue. of 15-PGDH activity is in human colorectal cancer tissues and matched normal lines were in the following HCT-15, HCT-116, HCA-7, and of cells was to a range of colorectal carcinoma lines with to 15-PGDH expression and prostaglandin and cells of and have high and levels of 15-PGDH cells levels of 15-PGDH and have been to to PGE2 J. H. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Finally, HCA-7 cells have high levels of COX-2 and prostaglandins as well as levels of 15-PGDH. To study the of 15-PGDH expression in we focused on indomethacin and ciglitazone, compounds to modulate 15-PGDH in other is a used with a of the of and COX-2 reports that indomethacin 15-PGDH expression in certain (14Quidville V. Segond N. Pidoux E. Cohen R. Jullienne A. Lausson S. Endocrinology. 2004; 145: 2561-2571Crossref PubMed Scopus (39) Google Scholar, M. Segond N. Pidoux E. Cohen R. Jullienne A. 2001; Scopus (32) Google Scholar, M. Pidoux E. C. Segond N. Jullienne A. Prostaglandins Leukotrienes Essent. Fatty Acids. 2001; Full Text PDF PubMed Scopus Google Scholar), and our results that indomethacin 15-PGDH expression in cells have no in HCA-7, HCT-15, and cells of 15-PGDH data by these that can modulate the expression of we examined the PPARγ with and with an Although previous reports that is a of 15-PGDH enzymatic activity with an of (17Cho H. Tai H.H. Prostaglandins Leukotrienes Essent. Fatty Acids. 2002; 67: 461-465Abstract Full Text PDF PubMed Scopus (32) Google Scholar), we a of this PPARγ on 15-PGDH expression in our studies To 15-PGDH may as a tumor suppressor we sought to identify pathways that expression of 15-PGDH. EGF is an of in a variety of human In pathways from the PGE2 have been to the EGF R. B. M. Nat. Med. 2002; 8: PubMed Scopus Google Scholar, Wang F. DuBois R.N. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We sought to identify stimulation of the modulate expression of 15-PGDH. Consistent with a role for EGF down-regulated 15-PGDH protein in and HCA-7 cells relative to the of this pathway with the to the increased expression of 15-PGDH in both and HCA-7 with for 1 to the of EGF blocked the of 15-PGDH with EGF To our this is the first observation that stimulation of the can prostaglandin of 15-PGDH and in of increased PGE2 production and of PGE2 degradation may local tissue levels of The of this to carcinogenesis in vivo is by our recent study that of ApcMin+/– mice with PGE2 significantly growth Wang H. S. B. Das DuBois R.N. Cancer 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). we 15-Pgdh levels in ApcMin+/– to decreased catabolism provide a for the of PGE2 on growth in Northern and Western of and C57BL/6-ApcMin+/– mouse that mice expression of 15-Pgdh The was in of ApcMin+/– in which the expression of 15-Pgdh was reduced with a normal maintained the expression of 15-Pgdh in these By contrast, both Cox-2 and protein levels were in the normal significantly increased within the A and is in light of the recent report that activity is increased in ApcMin+/– D.H. S.H. M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), with our observation that the of 15-PGDH of 15-PGDH in and in of 15-PGDH expression by EGF the functional of these To 15-PGDH protein levels correlate with enzymatic catabolism of 15-PGDH activity was in vitro as previously H.H. PubMed Scopus Google Scholar). The of cells with EGF for decreased 15-PGDH enzymatic activity by relative to cells the in protein levels these and that protein expression and enzymatic activity of 15-PGDH correlate in reports that genetic disruption of 15-Pgdh in the mouse results in increased tissue levels of PGE2 (10Coggins K.G. Latour A. Nguyen M.S. Audoly L. Coffman T.M. Koller B.H. Nat. Med. 2002; 8: 91-92Crossref PubMed Scopus (110) Google Scholar). To the loss of 15-PGDH expression PGE2 catabolism in we measured PGE-M, the urinary metabolite of PGE2 D.H. Morrow Biochem. 2004; PubMed Scopus Google Scholar). of from and C57BL/6-Pgdh–/– mice that is in from mice with for the hypothesis that loss of 15-PGDH expression can directly catabolism of PGE2 and contribute to elevated levels of bioactive of 15-PGDH and in to our in vivo studies and the of these we examined clinical of human colorectal carcinomas. A of human cancers and matched normal tissue reduced expression of 15-PGDH in malignant tissue relative to normal Northern and Western that 15-PGDH levels were decreased in of the of carcinoma with normal To the functional of these findings, 15-PGDH enzymatic activity was in human colorectal cancer tissues and matched normal 15-PGDH activity was found to changes in expression levels These data the hypothesis that 15-PGDH expression and activity are down-regulated in colorectal PGE2 levels are elevated significantly at of and these are to the increased expression of the The well of COX-2-derived PGE2 in malignant and disease a role in of stimulation of angiogenesis, and of tumor (6Sheng H. Shao J. Morrow J. Beauchamp R.D. DuBois R.N. Cancer Res. 1998; 58: 362-366PubMed Google Scholar, J.G. Chakraborty C. Lala P.K. Int. J. Cancer. 2001; 93: 497-506Crossref PubMed Scopus (209) Google Scholar). A large of has a in and from colorectal cancer in NSAIDs in the of colorectal cancers in are associated with high levels of and the of NSAIDs are at in to of cyclooxygenase-dependent formation of PGE2 B. L. J. Med. Google Scholar, S. PubMed Scopus Google Scholar, 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). virtually all studies have focused on by steady-state levels of PGE2 depend on the relative rates of biosynthesis and degradation of PGE2 by the rate-limiting 15-PGDH a mechanism for the local of The role of 15-PGDH in malignancy has been To our of prostaglandin function in carcinogenesis, the present study sought to the hypothesis that dysregulation of 15-PGDH is associated with colorectal We a variety of to our that 15-PGDH is down-regulated in colorectal cancer both in vitro and in human colorectal carcinoma cell ApcMin+/– and human colorectal cancer decreased 15-PGDH expression and activity relative to matched normal These the of 15-PGDH expression at the (11Rao C.V. Wang C.X. Simi B. Lubet R. Kelloff G. Steele V. Reddy B.S. Cancer Res. 1997; 57: 3717-3722PubMed Google Scholar) report that of 15-PGDH activity by the tumor in Although previous studies of 15-PGDH by indomethacin in certain (14Quidville V. Segond N. Pidoux E. Cohen R. Jullienne A. Lausson S. Endocrinology. 2004; 145: 2561-2571Crossref PubMed Scopus (39) Google Scholar, M. Segond N. Pidoux E. Cohen R. Jullienne A. 2001; Scopus (32) Google Scholar, M. Pidoux E. C. Segond N. Jullienne A. Prostaglandins Leukotrienes Essent. Fatty Acids. 2001; Full Text PDF PubMed Scopus Google Scholar), we of 15-PGDH by indomethacin in of colorectal carcinoma cell lines of cell lines and in vivo are to indomethacin 15-PGDH in the intestine. the of 15-PGDH expression and activity by EGF a previously mechanism by which regulate local PGE2 is to COX-2 R. M. L. G. J. R. PubMed Scopus Google Scholar), the study that EGF can the expression of 15-PGDH in with EGF in and HCA-7 are by data showing of 15-PGDH following of activity with Although the of studies on of recent data from S. Wang T. Cancer 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) the that of gene function can promote tumor formation. The loss of 15-PGDH expression in colorectal carcinomas is in light of previous reports that of in of colorectal cancers C. F. A. Oncol. 1998; 37: PubMed Scopus Google Scholar, A. T. Biol. 2000; 21: PubMed Scopus Google Scholar, R. F. N. Oncol. PubMed Scopus Google Scholar). The expression of is to associated with poor in patients with colorectal cancer A. M. E. G. K. H. Cancer. PubMed Scopus Google Scholar), and recent studies that inhibitors of have activity to patients with colorectal cancer are to other S. H. A. M. A. C. E. N. J. Med. 2004; PubMed Scopus Google Scholar). As several that are our present results may to the clinical of these These data may also with our report R.N. M. P. K. A. J. Google Scholar) that COX-2 is an growth gene in epithelial with of prostaglandin production following Other reports Wang F. DuBois R.N. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) from our group a mechanism whereby COX-2-derived PGE2 can the The present study that 15-PGDH is from EGFR, PGE2 to accumulate and this and have been in the of 15-PGDH A. S. B. K. B. J. 2003; PubMed Scopus (21) Google Scholar). studies of these of 15-PGDH in the intestine. in this that the of local PGE2 levels in human colorectal cancers is both increased expression of COX-2 and loss of 15-PGDH. Although 15-PGDH is to an role in such as parturition of local prostaglandin our data that 15-PGDH may cellular by local PGE2 at the tumor of increased PGE2 production and of PGE2 degradation to elevated levels of and the of this to carcinogenesis in vivo is by our recent study Wang H. S. B. Das DuBois R.N. Cancer 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) that of ApcMin+/– mice with PGE2 significantly ApcMin+/– mice develop and have elevated levels of PGE2 at that correlate with of H.L. Cancer Res. 2003; 63: Google Scholar). solely to elevated COX-2 our data in ApcMin+/– mice suggest that loss of 15-Pgdh also correlates with tumor progression in this that the loss of 15-Pgdh PGE2 our data also the hypothesis that 15-Pgdh an function degradation of of expression within the tumor with formation in a that can by with PGE2 Wang H. S. B. Das DuBois R.N. Cancer 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In summary, this study examines 15-PGDH expression in both normal and tumor tissues of the mouse and human with preliminary of 15-PGDH in We that 15-PGDH and protein levels are significantly reduced in human colorectal cancers relative to normal A in 15-PGDH expression is found within the tumor of in ApcMin+/– of 15-PGDH expression correlates with reduced enzymatic activity in vitro and in We also that the loss of 15-PGDH function in vivo of our data provide the first that reduced catabolism of PGE2 may promote colorectal These preliminary provide a novel for the of 15-PGDH expression and function in We Sanjoy and Beverly Koller for