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 highmobility 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. [Cancer Res 2007;67(9):3998-4004]

Targeted genomic analysis of Müllerian adenosarcoma

“…In addition, HMGA2 was amplified in at least one benign endometrial polyp, providing an alternative explanation for aberrantly expressing HMGA2 [57]. Interestingly, a transgenic mouse model expressing HMGA1 specifically in the uterus produced tumours bearing a striking histological resemblance to MA in all mice by 9 months of age [58]. There are potential therapeutic implications of our finding of HMGA2 overexpression in a subset of MAs, as a breast cancer cell line with high-level expression of HMGA2 has been shown to be highly sensitive to the topoisomerase II inhibitor doxorubicin [59].…”

The HMGA proteins: A myriad of functions (Review)

“…Hmga1a transgenic mice develop aggressive, highly penetrant lymphoid malignancy and HMGA1a is also overexpressed in human lymphoid leukemia (122,123). In addition to lymphoid malignancy, Hmga1a transgenic mice develop uterine tumors, which resemble human uterine adenosarcomas (124). In most high-grade, but not in benign or most low-grade human uterine adenosarcomas, significant overexpression of HMGA1a is detected (124).…”

HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels

“…Indeed, it has been reported that the blockage of their expression prevents thyroid cell transformation and promotes the death of malignant cells (6)(7). Transgenic mice overexpressing either HMGA1 or HMGA2 develop uterine tumours, haematopoietic tumours, and pituitary adenomas (8)(9)(10)(11).…”