title: Suppression of carbonyl reductase expression enhances malignant behaviour in uterine cervical squamous cell carcinoma: carbonyl reductase predicts prognosis and lymph node metastasis.
abstract: Carbonyl reductase (CR) is an NADPH-dependent, mostly monomeric, cytosolic enzyme with broad substrate specificity for carbonyl compounds. CR appears to be involved in the regulation of tumour progression. However, molecular mechanisms of CR in tumour progression and clinical significance of CR status remain unclear in human uterine squamous cell carcinoma (SCC). Here, we investigated the clinical significance of CR using immunohistochemical analyses of human uterine cervical SCC tissues and how CR affects cancer cell behaviour in vitro. Paraffin sections from uterine cervical SCC tissues, FIGO stage Ib1-IIb (n = 67) were immunostained with anti-CR antibodies. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Sense and antisense CR cDNAs were transfected into a human uterine SCC cell line (SiHa) to investigate the role of CR in cancer cell invasion and metastasis. Immunohistochemical analyses showed that reduced CR expression patterns in primary cancer lesions were closely associated with a high incidence of pelvic lymph node metastasis, poor OS, and poor PFS. In an in vitro experiment, suppression of CR increased cancer cell invasion, secretion of MMP-2, -9 and cyclooxygenase-2 (COX-2) expression and decreased E-cadherin expression. On the other hand, over-expression of CR increased E-cadherin expression and decreased MMP-2, -9 secretion and COX-2 expression. The reduced CR expression pattern, as measured by immunohistochemistry, can be a useful predictor of lymph node metastasis and poor prognosis in patients with uterine SCC. This clinical result is supported by the in vitro data which show that suppression of CR expression promotes cancer cell invasion with decreased E-cadherin expression and increased MMP-2, -9 secretion.
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube 755-8505, Japan. muraaki@yamaguchi-u.ac.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Murakami
authors.forename: Chikako
authors.initials: C
authors.lastname: Fukushima
authors.forename: Keiko
authors.initials: K
authors.lastname: Yoshidomi
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sueoka
authors.forename: Shugo
authors.initials: S
authors.lastname: Nawata
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsuchida
authors.forename: Endom
authors.initials: E
authors.lastname: Ismail
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sugino
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016373:DNA, Antisense / Q000008:administration & dosage / Q000235:genetics; D018572:Disease-Free Survival; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018093:Gelatinases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D011379:Prognosis; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D015820:Cadherins; D052246:Cyclooxygenase 2 Inhibitors; D016373:DNA, Antisense; D004792:Enzyme Precursors; D000429:Alcohol Oxidoreductases; D051546:Cyclooxygenase 2; D018093:Gelatinases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9