15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice
Autor: | Benny Chong, Romina Vincenti, Hsin-Hsiung Tai, Guido Eibl, Hung Pham, Lee W. Slice |
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Rok vydání: | 2007 |
Předmět: |
Cancer Research
Angiogenesis medicine.medical_treatment Mice Nude medicine.disease_cause Prostaglandin E synthase Mice medicine In Situ Nick-End Labeling Animals Prostaglandin E2 Phosphorylation Cyclic AMP Response Element-Binding Protein Molecular Biology DNA Primers biology Base Sequence Cell growth Kinase Reverse Transcriptase Polymerase Chain Reaction Neoplasms Experimental Molecular biology Immunohistochemistry Rats Genes ras Biochemistry Apoptosis biology.protein Hydroxyprostaglandin Dehydrogenases Prostaglandins lipids (amino acids peptides and proteins) Mitogen-Activated Protein Kinases Carcinogenesis Cell Division medicine.drug Prostaglandin E |
Zdroj: | Molecular carcinogenesis. 47(6) |
ISSN: | 1098-2744 |
Popis: | Oncogenic Ras mutations are early genetic events in colorectal cancer that induce cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) biosynthesis. PGE(2), a downstream product of COX-2, promotes cancer progression by modulating proliferation, apoptosis and angiogenesis. 15-hydroxyprostaglandin dehydrogenase (PGDH) degrades PGE(2) and is down-regulated in colorectal cancer, suggesting that PGDH plays a role in regulating PGE(2) levels and that PGDH over-expression could attenuate Ras-mediated tumorigenesis. Lentiviral transduction was used to express GFP (18.GFP), K-Ras(V12) (18.K-Ras(V12)), PGDH (18.PGDH) or both K-Ras(V12) and PGDH (18.K-Ras(V12).PGDH) in nontumorigenic rat intestinal epithelial (IEC-18) cells. 18.K-Ras(V12) cells exhibited increased phosphorylation of MAP kinases and CREB, proliferation rates, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 expression and PGE(2) and PGI(2) levels. 18.PGDH and 18.K-Ras(V12).PGDH cells had 10(4)-fold increases in PGDH activity with decreased PGE(2) and PGI(2) levels, COX-2 and mPGES-1 expression and proliferation rates. 18.GFP, 18.PGDH, and 18.K-Ras(V12).PGDH cells were unable to grow in soft agar media whereas 18.K-Ras(V12) cells exhibited anchorage-independent cell growth. Xenografts of implanted 18.K-Ras(V12) cells in nu/nu mice produced rapid (2 wk) tumors with uniform antibody staining for COX-2 and mPGES-1 throughout the tumor and elevated PGE(2) levels. Xenografts of 18.K-Ras(V12).PGDH cells exhibited delayed (8 wk) tumor formation with negligible COX-2 and mPGES-1 expression and significantly decreased PGE(2) levels. 18.K-Ras(V12).PGDH tumors had decreased staining of the proliferative marker, Ki-67, and a significant increase in apoptosis in the central region of the tumor. Based on these data, we conclude that PGDH expression suppresses K-Ras(V12)-mediated tumorigenesis in intestinal epithelial cells. |
Databáze: | OpenAIRE |
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