TY - JOUR
T1 - The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors
AU - Hillion, Joelle
AU - Roy, Sujayita
AU - Heydarian, Mohammad
AU - Cope, Leslie
AU - Xian, Lingling
AU - Koo, Michael
AU - Luo, Li Z.
AU - Kellyn, Kathleen
AU - Ronnett, Brigitte M.
AU - Huso, Tait
AU - Armstrong, Deborah
AU - Reddy, Karen
AU - Huso, David L.
AU - Resar, L. M.S.
N1 - Funding Information:
The authors thank the generous support of the NIH, Prevent Cancer Foundation, and the Maryland Stem Cell Research Fund. Grant support: R01 CA092339, R21 CA118343, R03 CA139331 (L.M.S. Resar), CA149550, P01 CA134292 (D. L. Huso), Prevent Cancer Foundation (J. Hillion), Maryland Stem Cell Research Fund (J. Hillion, L. Xian, S. N. Shah, and L. Resar)
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6
Y1 - 2016/6
N2 - 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 Matrix Metalloproteinase (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.
AB - 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 Matrix Metalloproteinase (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.
KW - Chromatin remodeling proteins
KW - HMGA1
KW - High Mobility Group A1
KW - MMP-2
KW - Tumor progression
KW - Uterine cancer
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U2 - 10.1016/j.ygyno.2016.03.020
DO - 10.1016/j.ygyno.2016.03.020
M3 - Article
C2 - 27001612
AN - SCOPUS:84975488001
SN - 0090-8258
VL - 141
SP - 580
EP - 587
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 3
ER -