Work

Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells

Year: 2016

Type: article

Abstract: Cancer stem cells are a subpopulation of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. The aim of this study was to investigate the role of HMGA1, a chromatin remodeling factor abundantly expressed in many different cancers, in the regulation of cancer stem cells in ovarian cancer. Spheroid-forming cancer stem cells were isolated from A2780, SKOV3 and PA1 ovarian cancer cells by three-dimensional spheroid culture. Elevated expression of HMGA1 was observed in spheroid cells along with increased expression of stemness-related genes, such as SOX2, KLF4, ALDH, ABCB1 and ABCG2. Furthermore, spheroid A2780 cells, compared with adherent cells, showed higher resistance to chemotherapeutic agents such as paclitaxel and doxorubicin. HMGA1 knockdown in spheroid cells reduced the proliferative advantage and spheroid-forming efficiency of the cells and the expression of stemness-related genes. HMGA1 overexpression in adherent A2780 cells increased cancer stem cell properties, including proliferation, spheroid-forming efficiency and the expression of stemness-related genes. In addition, HMGA1 regulated ABCG2 promoter activity through HMGA1-binding sites. Knockdown of HMGA1 in spheroid cells reduced resistance to chemotherapeutic agents, whereas the overexpression of HMGA1 in adherent ovarian cancer cells increased resistance to chemotherapeutic agents in vitro. Furthermore, HMGA1-overexpressing A2780 cells showed a significant survival advantage after chemotherapeutic agent treatment in a xenograft tumorigenicity assay. Together, our results provide novel insights regarding the critical role of HMGA1 in the regulation of the cancer stem cell characteristics of ovarian cancer cells, thus suggesting that HMGA1 may be an important target in the development of therapeutics for ovarian cancer patients. A gene associated with stem cell identity may also offer a useful marker for aggressive, treatment-resistant ovarian tumor cells. ‘Cancer stem cells’ (CSCs) are less vulnerable to chemotherapy, and actively contribute to tumor growth and spread. Researchers led by Jae Ho Kim at Pusan National University in Korea developed a strategy for cultivating cells that closely resemble ovarian CSCs. They determined that these cells produce elevated levels of a protein called HMGA1, which appears to help them maintain their stem cell-like identity. HMGA1 also controls production of proteins that help cells eliminate toxic drugs. Following implantation into mice, HMGA1-deficient CSCs proved more vulnerable to chemotherapy than unmodified CSCs. These findings suggest that HMGA1 may offer a useful target for identifying ovarian CSCs in patients, perhaps even rendering them more vulnerable to therapeutic agents.

Source: Experimental & Molecular Medicine

DOI: 10.1038/emm.2016.73