title: Crucial role of HMGA1 in the self-renewal and drug resistance of ovarian cancer stem cells.
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.
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Dae Kyoung
authors: DK
authors: Kim
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Eun Jin
authors: EJ
authors: Seo
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Eun J
authors: EJ
authors: Choi
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Su In
authors: SI
authors: Lee
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Yang Woo
authors: YW
authors: Kwon
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Il Ho
authors: IH
authors: Jang
authors: Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Seung-Chul
authors: SC
authors: Kim
authors: Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Ki-Hyung
authors: KH
authors: Kim
authors: Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Dong-Soo
authors: DS
authors: Suh
authors: Department of Nuclear Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors: Kim
authors: K
authors: Seong-Jang
authors: Functional Genomics Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
authors: Sang Chul
authors: SC
authors: Lee
authors: Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.|Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.
authors: Jae Ho
authors: JH
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D025741:HMGA1a Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D025741:HMGA1a Protein