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

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 Hmga1 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.

HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer

“…Even through a recent study showed miR-221 could suppress the expression of MMP2 74 , our reporter assay showed that neither miR-221-3p nor miR-222-3p had an effect on the 3′UTR of MMP2. Otherwise, recent studies indicated that HMGA1 could promote the migration and invasion in lung cancer and uterine carcinomas by directly targeted MMP2 as well as in pancreatic adenocarcinoma and gliomas through regulating MMP9 17 , 75 – 77 . Similarly, our results revealed that HMGA1 regulated the expression of MMP2 and MMP9.…”

miR‐214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells

“…HMGA1 helps promote protumourigenic phenomena like proliferation, migration, and invasion in multiple ways: it activates the Akt/MMP9 cascade in pancreatic adenocarcinoma, HMGA1/MMP2 pathway in uterine carcinosarcomas, and blocks the expression of metastasis suppressor protein 1 in T‐cell leukaemia . Further, HMGA1 expression has been found to be induced by transforming growth factor beta (TGF‐β) signalling through specificity protein 1 and phosphatidyl inositol‐3 kinase, resulting in enhanced tumourigenic properties in breast carcinoma .…”

HMGA1 Overexpression is Associated With the Malignant Status and Progression of Breast Cancer

“…Breast cancer represents the most common cancer and is one of the leading causes of cancer mortality in women. Although the survival of breast cancer patients has improved due to advancements in diagnosis and treatment, the prognosis in many patients with breast cancer remains poor (Hillion et al, 2016). It has been reported that genetic markers including estrogen receptor (ER) (Deroo et al, 2006), BRCA (Miecznikowski et al, 2010), and HER-2/neu receptor (Hynes et al, 1994) were significantly associated with breast cancer severity.…”