| First Author | Sasaki Y | Year | 2012 |
| Journal | Oncogene | Volume | 31 |
| Issue | 24 | Pages | 2943-52 |
| PubMed ID | 21986945 | Mgi Jnum | J:186134 |
| Mgi Id | MGI:5431064 | Doi | 10.1038/onc.2011.472 |
| Citation | Sasaki Y, et al. (2012) Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis. Oncogene 31(24):2943-52 |
| abstractText | Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E(2) is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE(2)-biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of beta-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D(2) and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MPhis) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MPhis and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MPhis failed to facilitate tumor growth. The adoptive transfer of WT BM-MPhis into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MPhis is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers. |
