title: Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance.
abstract: Human carbonyl reductase 1 (CBR1) is an enzyme that catalyse the reduction of many compounds by using NADPH-dependent oxydoreductase activity. Although CBR1 is known to regulate the tumour progression, the molecular mechanisms of CBR1 in cancer progression and the clinical significance of CBR1 status remain unclear. Here, we investigated the molecular mechanisms by which CBR1 affects cancer cell behaviour in vitro and the clinical significance of CBR1 using immunohistochemical analyses in endometrial cancer. Here, the role of CBR1 in cancer cell invasion and metastasis, and its molecular mechanisms were investigated by transfection of sense and antisense CBR1 cDNAs into a human endometrial adenocarcinoma cell line. The relationship between CBR1 expression analysed by immunohistochemistry and prognosis such as progression free survival (PFS) and overall survival (OS) was examined in endometrial cancer tissues from FIGO stage I-IV (n=109). Suppression of CBR1 by antisense CBR1 cDNA increased cancer cell invasion, and suppressed E-cadherin expression and capacity for cellular aggregation. In contrast, over-expression of CBR1 by sense CBR1 cDNA increased E-cadherin expression and capacity for cellular aggregation, and suppressed cancer cell invasion. The expression of transcriptional suppressors of E-cadherin, Snail and ZEB1, were increased by CBR1 suppression, but suppressed by CBR1 over-expression. Immunohistochemical analyses showed that decreased CBR1 expression is significantly related with poor PFS and OS compared with strong CBR1 expression. In multivariate analyses, decreased CBR1 expression was an independent prognostic factor for PFS and OS. CBR1 regulates cancer cell invasion in endometrial adenocarcinomas by regulating the epithelial mesenchymal transition. A decreased CBR1 expression can be a useful marker of an unfavourable clinical outcome in patients with endometrial cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan. Electronic address: muraaki@yamaguchi-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Murakami
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yakabe
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yoshidomi
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sueoka
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Nawata
authors.affiliation: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Second Department of Biochemistry, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki 036-8562, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsuchida
authors.affiliation: Department of Pathology, University of Kuwait, PO Box 24923, Safat 13110, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sugino
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000429:Alcohol Oxidoreductases / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human