The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis

Abeba Tesfaye, Francescopaolo Di Cello, Joelle Hillion, Brigitte Maria Ronnett, Ossama Elbahloul, Raheela Ashfaq, Surajit Dhara, Edward Prochownik, Kathryn Tworkoski, Raymond Reeves, Richard S Roden, Lora Hedrick Ellenson, David L. Huso, Linda M Smith Resar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3998-4004
Number of pages7
JournalCancer Research
Volume67
Issue number9
DOIs
StatePublished - May 1 2007

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Cyclooxygenase 2
Uterine Neoplasms
Carcinogenesis
Up-Regulation
Genes
Neoplasms
Uterus
HMGA1a Protein
Methylcellulose
Leiomyosarcoma
Chromatin Immunoprecipitation
Oncogenes
Transgenic Mice
Transfection
Cause of Death
Gene Expression
Messenger RNA
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis. / Tesfaye, Abeba; Di Cello, Francescopaolo; Hillion, Joelle; Ronnett, Brigitte Maria; Elbahloul, Ossama; Ashfaq, Raheela; Dhara, Surajit; Prochownik, Edward; Tworkoski, Kathryn; Reeves, Raymond; Roden, Richard S; Ellenson, Lora Hedrick; Huso, David L.; Smith Resar, Linda M.

In: Cancer Research, Vol. 67, No. 9, 01.05.2007, p. 3998-4004.

Research output: Contribution to journalArticle

Tesfaye, A, Di Cello, F, Hillion, J, Ronnett, BM, Elbahloul, O, Ashfaq, R, Dhara, S, Prochownik, E, Tworkoski, K, Reeves, R, Roden, RS, Ellenson, LH, Huso, DL & Smith Resar, LM 2007, 'The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis', Cancer Research, vol. 67, no. 9, pp. 3998-4004. https://doi.org/10.1158/0008-5472.CAN-05-1684
Tesfaye, Abeba ; Di Cello, Francescopaolo ; Hillion, Joelle ; Ronnett, Brigitte Maria ; Elbahloul, Ossama ; Ashfaq, Raheela ; Dhara, Surajit ; Prochownik, Edward ; Tworkoski, Kathryn ; Reeves, Raymond ; Roden, Richard S ; Ellenson, Lora Hedrick ; Huso, David L. ; Smith Resar, Linda M. / The high-mobility group A1 gene up-regulates cyclooxygenase 2 expression in uterine tumorigenesis. In: Cancer Research. 2007 ; Vol. 67, No. 9. pp. 3998-4004.
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AU - Tesfaye, Abeba

AU - Di Cello, Francescopaolo

AU - Hillion, Joelle

AU - Ronnett, Brigitte Maria

AU - Elbahloul, Ossama

AU - Ashfaq, Raheela

AU - Dhara, Surajit

AU - Prochownik, Edward

AU - Tworkoski, Kathryn

AU - Reeves, Raymond

AU - Roden, Richard S

AU - Ellenson, Lora Hedrick

AU - Huso, David L.

AU - Smith Resar, Linda M

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N2 - 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.

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