title: Esophageal cancer proliferation is mediated by cytochrome P450 2C9 (CYP2C9).
abstract: Cytochrome P450 epoxygenases (CYP450) have been recently shown to promote malignant progression. Here we investigated the mRNA and protein expression and potential clinical relevance of CYP2C9 in esophageal cancer. Highest expression was detected in esophageal adenocarcinoma (EAC; n=78) and adjacent esophageal mucosa (NEM; n=79). Levels of CYP2C9 in EAC and NEM were significantly higher compared to esophageal squamous cell carcinoma (ESCC; n=105). Early tumor stages and well-differentiated tumors showed a significantly higher CYP2C9 expression compared to progressed tumors. Moreover, CYP2C9 expression was correlated to high Ki-67 labeling indices in EAC and Ki-67 positive tumor cells in EAC and ESCC. Selective inhibition of CYP2C9 decreased tumor cell proliferation (KYSE30, PT1590 and OE19) in vitro, which was abolished by 11,12-epoxyeicosatrienoic acid (11,12-EET). Cell-cycle analysis using FACS revealed that inhibition of CYP2C9 leads to a G0/G1 phase cell-cycle arrest. CYP2C9 seems to be relevant for early esophageal cancer development by promoting tumor cell proliferation. Pharmacological inhibition of CYP2C9 might contribute to a more efficient therapy in CYP2C9 highly expressing esophageal cancers.
authors.affiliation: Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany. nikolas.stoecklein@med.uni-duesseldorf.de
authors.forename: Moritz
authors.initials: M
authors.lastname: Schmelzle
authors.forename: Levent
authors.initials: L
authors.lastname: Dizdar
authors.forename: Hanno
authors.initials: H
authors.lastname: Matthaei
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Baldus
authors.forename: Judith
authors.initials: J
authors.lastname: Wolters
authors.forename: Nina
authors.initials: N
authors.lastname: Lindenlauf
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.forename: Ron-Patrick
authors.initials: RP
authors.lastname: Cadeddu
authors.forename: Feride
authors.initials: F
authors.lastname: Kröpil
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Topp
authors.forename: Jan
authors.initials: J
authors.lastname: Schulte am Esch
authors.forename: Claus F
authors.initials: CF
authors.lastname: Eisenberger
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.forename: Nikolas H
authors.initials: NH
authors.lastname: Stoecklein
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065729:Cytochrome P-450 CYP2C9; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D016193:G1 Phase; D006801:Humans; D007150:Immunohistochemistry; D016192:Resting Phase, Cell Cycle
chemical_list: C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D015126:8,11,14-Eicosatrienoic Acid