title: Aberrant hypomethylation-mediated AGR2 overexpression induces an aggressive phenotype in ovarian cancer cells.
abstract: The metastatic properties of cancer cells result from genetic and epigenetic alterations that lead to the abnormal expression of key genes regulating tumor phenotypes. Recent discoveries suggest that aberrant DNA methylation provides cancer cells with advanced metastatic properties; however, the precise regulatory mechanisms controlling metastasis-associated genes and their roles in metastatic transformation are largely unknown. We injected SK-OV-3 human ovarian cancer cells into the perineum of nude mice to generate a mouse model that mimics human ovarian cancer metastasis. We analyzed the mRNA expression and DNA methylation profiles in metastasized tumor tissues in the mice. The pro-oncogenic anterior gradient 2 (AGR2) gene showed increased mRNA expression and hypomethylation at CpG sites in its promoter region in the metastatic tumor tissues compared with the cultured SK-OV-3 cells. We identified crucial cytosine residues at CpG sites in the AGR2 promoter region. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reduced the level of CpG methylation in the AGR2 promoter and increased the level of AGR2 expression. Next, we explored the functional role of AGR2 in the metastatic transformation of SK-OV-3 cells. SK-OV-3 cells overexpressing AGR2 showed increased migratory and invasive activity. Our results indicate that DNA methylation within the AGR2 promoter modulates more aggressive cancer cell phenotypes.
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, 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, 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, Seoul 158-710, Republic of Korea.
authors.forename: Dahyun
authors.initials: D
authors.lastname: Lyu
authors.affiliation: College of Pharmacy, Sunchon National University, Jeonnam 540-742, Republic of Korea.
authors.forename: Ae Kyung
authors.initials: AK
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University, 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, Seoul 158-710, Republic of Korea.
authors.forename: Jung-Hyuck
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*
chemical_list: C502296:AGR2 protein, human; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D000077209:Decitabine; D001374:Azacitidine