title: 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1.
abstract: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in prostaglandin (PG) metabolism. This study provides important evidence for inhibition of hepatocellular carcinoma (HCC) growth by 15-PGDH through the 15-keto-prostaglandin E2 (15-keto-PGE2)/peroxisome proliferator-activated receptor-γ (PPARγ)/p21(WAF1/Cip1) signaling pathway. Forced overexpression of 15-PGDH inhibited HCC cell growth in vitro, whereas knockdown of 15-PGDH enhanced tumor growth parameters. In a tumor xenograft model in severe combined immunodeficiency mice, inoculation of human HCC cells (Huh7) with overexpression of 15-PGDH led to significant inhibition of tumor growth, whereas knockdown of 15-PGDH enhanced tumor growth. In a separate tumor xenograft model in which mouse HCC cells (Hepa1-6) were inoculated into syngeneic C57BL/6 mice, intratumoral injection of adenovirus vector expressing 15-PGDH (pAd-15-PGDH) significantly inhibited xenograft tumor growth. The antitumor effect of 15-PGDH is mediated through its enzymatic product, 15-keto-PGE2, which serves as an endogenous PPARγ ligand. Activation of PPARγ by 15-PGDH-derived 15-keto-PGE2 enhanced the association of PPARγ with the p21(WAF1/Cip1) promoter and increased p21 expression and association with cyclin-dependent kinase 2 (CDK2), CDK4 and proliferating cell nuclear antigen. Depletion of p21 by short hairpin RNA reversed 15-PGDH-induced inhibition of HCC cell growth; overexpression of p21 prevented 15-PGDH knockdown-induced tumor cell growth. These results show a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21(WAF1/Cip1) signaling cascade that regulates hepatocarcinogenesis and tumor progression.
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA [2] Tongji University School of Life Science and Technology, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C026346:15-ketoprostaglandin E2; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone
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