title: FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors.
abstract: FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Kitade
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan. ichirou@med.kyushu-u.ac.jp.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tsunematsu
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Asanoma
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Sonoda
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Department of Obstetrics and Gynecology, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
mesh_terms: D000328:Adult; D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases
keywords: FBXW7; methylation; mutation; ovarian cancer; p53