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.
Highlights
High-mobility group A gene (HMGA) expression is increased in a variety of human cancers (1–9), its role in the pathogenesis of these malignancies has not been clearly delineated.Note: Supplementary data for this article are available at Cancer Research Online.The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms (1), which function as architectural chromatin-binding proteins involved in regulating gene expression (10–13)
The transgene was highly expressed in the uteri; both HMGA1a mRNA (Fig. 1A) and protein (Fig. 1A and B) levels were increased in the transgenic uteri compared with control uteri
We found that cyclooxygenase 2 (COX-2) mRNA and protein were significantly increased in the fibroblasts overexpressing HMGA1a, but not in the fibroblasts infected with the control vector (Supplementary Fig. S3)
Summary
High-mobility group A gene (HMGA) expression is increased in a variety of human cancers (1–9), its role in the pathogenesis of these malignancies has not been clearly delineated. There are no known differences in the biological activities of these isoforms (1, 4) Both proteins contain AT hook DNA-binding domains that mediate binding to AT-rich regions in the minor groove of chromosomal DNA (10–13). After binding to DNA, the HMGA1 proteins recruit additional transcription factors, and in concert with these factors, alter gene expression (10–13). This gene is located on the short arm of chromosome 6, in a region known to be involved in amplifications, rearrangements, translocations, and other abnormalities correlated with human cancers (1). We found that cyclooxygenase 2 (COX-2) is an important mediator of HMGA1a function in uterine tumorigenesis These studies underscore the oncogenic properties of HMGA1 in a variety of tissues. Our transgenic mice should provide a useful model system to identify other molecular pathways that lead to uterine cancer
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