Joelle Hillion1, Sujayita Roy1, Mohammad Heydarian2, Leslie Cope3, Lingling Xian1, Michael Koo1, Li Z Luo1, Kathleen Kellyn4, Brigitte M Ronnett5, Tait Huso1, Deborah Armstrong3, Karen Reddy6, David L Huso7, L M S Resar8. 1. Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 2. Department of Biologic Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 3. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 4. Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 5. Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 6. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Biologic Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 7. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. 8. Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: lresar@jhmi.edu.
Abstract
OBJECTIVES: Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1a transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. METHODS: To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). RESULTS: Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells. CONCLUSIONS: Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.
OBJECTIVES: Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1atransgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. METHODS: To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). RESULTS: Here, we report for the first time that uterine tumor growth is impaired in Hmga1atransgenic mice crossed on to an Mmp-2 deficient background. In humantumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in humancarcinosarcoma cells. CONCLUSIONS: Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of humancarcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.
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