title: The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis.
abstract: Uterine cancer is the most common cancer of the female genital tract and is the fourth most frequent cause of cancer death in women in the U.S. Despite the high prevalence of uterine cancers, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. Moreover, there are limited mouse models to study these malignancies. We generated transgenic mice with high-mobility group A1 gene (HMGA1a) expression targeted to uterine tissue and all female mice developed tumors by 9 months of age. Histopathologically, the tumors resemble human uterine adenosarcoma and are transplantable. To determine whether these findings are relevant to human disease, we evaluated primary human uterine neoplasms and found that HMGA1a mRNA and protein levels are increased in most high-grade neoplasms but not in normal uterine tissue, benign tumors, or most low-grade neoplasms. We also found that HMGA1a up-regulates cyclooxygenase 2 (COX-2) expression in transgenic tumors. Moreover, both HMGA1a and COX-2 expression are up-regulated in high-grade human leiomyosarcomas. Using chromatin immunoprecipitation, HMGA1a binds directly to the COX-2 promoter in human uterine cancer cells in vivo and activates its expression in transfection experiments. We also show that blocking either HMGA1a or COX-2 in high-grade human uterine cancer cells blocks anchorage-independent cell growth in methylcellulose. These findings show that HMGA1a functions as an oncogene when overexpressed in the uterus and contributes to the pathogenesis of human uterine cancer by activating COX-2 expression. Although a larger study is needed to confirm these results, HMGA1a may be a useful marker for aggressive human uterine cancers.
authors.affiliation: Hematology Division, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Abeba
authors.initials: A
authors.lastname: Tesfaye
authors.forename: Francescopaolo
authors.initials: F
authors.lastname: Di Cello
authors.forename: Joelle
authors.initials: J
authors.lastname: Hillion
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Ronnett
authors.forename: Ossama
authors.initials: O
authors.lastname: Elbahloul
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Surajit
authors.initials: S
authors.lastname: Dhara
authors.forename: Edward
authors.initials: E
authors.lastname: Prochownik
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tworkoski
authors.forename: Raymond
authors.initials: R
authors.lastname: Reeves
authors.forename: Richard
authors.initials: R
authors.lastname: Roden
authors.forename: Lora Hedrick
authors.initials: LH
authors.lastname: Ellenson
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Linda M S
authors.initials: LM
authors.lastname: Resar
mesh_terms: D018195:Adenosarcoma / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D014162:Transfection; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D025741:HMGA1a Protein; D051546:Cyclooxygenase 2