Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma

被引:37
作者
Zhang, Lin [1 ]
Li, Hong [1 ]
Ge, Chao [1 ]
Li, Meng [1 ]
Zhao, Fang-yu [1 ]
Hou, He-lei [1 ]
Zhu, Miao-xin [1 ]
Tian, Hua [1 ]
Zhang, Li-xing [1 ]
Chen, Tao-yang [2 ]
Jiang, Guo-ping [3 ]
Xie, Hai-yang [3 ]
Cui, Ying [4 ]
Yao, Ming [1 ]
Li, Jin-jun [1 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst,Renji Hosp, Shanghai 200030, Peoples R China
[2] Qi Dong Liver Canc Inst, Qi Dong, Peoples R China
[3] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Gen Surg, Hangzhou 310003, Zhejiang, Peoples R China
[4] Canc Inst Guangxi, Nanning, Peoples R China
基金
中国国家自然科学基金;
关键词
Ikaros; CD133; hepatocellular carcinoma; cancer stem cells; TUMOR-INITIATING CELLS; GROWTH-FACTOR-BETA; STEM/PROGENITOR CELLS; EPIGENETIC REGULATION; COREPRESSOR CTBP; PROSTATE-CANCER; DNA-BINDING; IN-VITRO; GENE; ACTIVATION;
D O I
10.18632/oncotarget.2524
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikaros inhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133(+) cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaros was significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy.
引用
收藏
页码:10621 / 10635
页数:15
相关论文
共 52 条
[11]   CtBP1 Interacts with Ikaros and Modulates Pituitary Tumor Cell Survival and Response to Hypoxia [J].
Dorman, Katie ;
Shen, Zhongyi ;
Yang, Caimei ;
Ezzat, Shereen ;
Asa, Sylvia L. .
MOLECULAR ENDOCRINOLOGY, 2012, 26 (03) :447-457
[12]   Notch activation is an early and critical event during T-cell leukemogenesis in Ikaros-deficient mice [J].
Dumortier, A ;
Jeannet, R ;
Kirstetter, P ;
Kleinmann, E ;
Sellars, M ;
dos Santos, NR ;
Thibault, C ;
Barths, J ;
Ghysdael, J ;
Punt, JA ;
Kastner, P ;
Chan, S .
MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (01) :209-220
[13]   An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth [J].
Ezzat, S ;
Mader, R ;
Fischer, S ;
Yu, SJ ;
Ackerley, C ;
Asa, SL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (07) :2214-2219
[14]   Ikaros isoforms in human pituitary tumors - Distinct localization, histone acetylation, and activation of the 5′ fibroblast growth factor receptor-4 promoter (Publication with Expression of Concern) [J].
Ezzat, S ;
Yu, SJ ;
Asa, SL .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 163 (03) :1177-1184
[15]   IKAROS, AN EARLY LYMPHOID-SPECIFIC TRANSCRIPTION FACTOR AND A PUTATIVE MEDIATOR FOR T-CELL COMMITMENT [J].
GEORGOPOULOS, K ;
MOORE, DD ;
DERFLER, B .
SCIENCE, 1992, 258 (5083) :808-812
[16]   Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation [J].
Gopisetty, G. ;
Xu, J. ;
Sampath, D. ;
Colman, H. ;
Puduvalli, V. K. .
ONCOGENE, 2013, 32 (26) :3119-3129
[17]   Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells [J].
Grund, EM ;
Spyropoulos, DD ;
Watson, DK ;
Muise-Helmericks, RC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (06) :4772-4778
[18]   CD13 is a therapeutic target in human liver cancer stem cells [J].
Haraguchi, Naotsugu ;
Ishii, Hideshi ;
Mimori, Koshi ;
Tanaka, Fumiaki ;
Ohkuma, Masahisa ;
Kim, Ho Min ;
Akita, Hirofumi ;
Takiuchi, Daisuke ;
Hatano, Hisanori ;
Nagano, Hiroaki ;
Barnard, Graham F. ;
Doki, Yuichiro ;
Mori, Masaki .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (09) :3326-3339
[19]   Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling [J].
Hu, Chen ;
Li, Hong ;
Li, Jinjun ;
Zhu, Zheng ;
Yin, Shengyong ;
Hao, Xiangfang ;
Yao, Ming ;
Zheng, Shusen ;
Gu, Jianren .
CARCINOGENESIS, 2008, 29 (12) :2289-2297
[20]   Expression and possible role of ets-1 in hepatocellular carcinoma [J].
Ito, Y ;
Miyoshi, E ;
Takeda, T ;
Sakon, M ;
Noda, K ;
Tsujimoto, M ;
Monden, M ;
Taniguchi, N ;
Matsuura, N .
AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2000, 114 (05) :719-725