title: Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer.
abstract: A lack of reliable biomarkers for the early detection and risk of metastatic recurrences makes ovarian cancer the most lethal gynecological cancer. To understand the molecular mechanisms involved in ovarian cancer metastasis in vivo, we analyzed the transcriptional expression pattern in metastatic implants of human ovarian carcinoma xenografts in mice. The expression of 937 genes was significantly different, by at least 2-fold, in the xenografts compared with that in SK-OV-3 cells. We investigated the mechanisms that regulate the expression of one of the profoundly upregulated genes, interferon-induced transmembrane protein 1 (IFITM1), in the metastatic implants. Specific CpG sites within the IFITM1 promoter were hypomethylated in the metastatic implants relative to those in the wild-type SK-OV-3 cells. Treating wild-type SK-OV-3 cells with the demethylating agent 5-aza-2'-deoxycytidine enhanced IFITM1 expression in a dose-dependent manner, implying transcriptional regulation by promoter methylation. We also found that IFITM1 overexpression caused increased migration and invasiveness in SK-OV-3 cells. Our results demonstrate that IFITM1 could be a novel metastasis-promoting gene that enhances the metastatic phenotype in ovarian cancer via epigenetic transcriptional regulation. Our findings also suggest that the status of DNA methylation within the IFITM1 promoter region could be a biomarker indicating metastatic progression in ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Hye Youn
authors.initials: HY
authors.lastname: Sung
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Eun Nam
authors.initials: EN
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Dahyun
authors.initials: D
authors.lastname: Lyu
authors.affiliation: Department of Radiology and Research, Institute of Radiology, University of Ulsan, College of Medicine, Asan Medical Center, Songpa-ku, Seoul 138-736, Republic of Korea.
authors.forename: Hyuck Jae
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Woong
authors.initials: W
authors.lastname: Ju
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Yangcheon‑ku, Seoul 158-710, Republic of Korea.
authors.forename: Jung-Hyuck
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D000077209:Decitabine; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010053:Ovary / Q000473:pathology; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000943:Antigens, Differentiation; D014408:Biomarkers, Tumor; C062010:leu-13 antigen; D000077209:Decitabine; D001374:Azacitidine