RRC ID 77179
Author Zhang L, Li H, Ge C, Li M, Zhao FY, Hou HL, Zhu MX, Tian H, Zhang LX, Chen TY, Jiang GP, Xie HY, Cui Y, Yao M, Li JJ.
Title Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma.
Journal Oncotarget
Abstract 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 Ikarosinhibited 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 Ikaroswas 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.
Volume 5(21)
Pages 10621-35
Published 2014-11-15
DOI 10.18632/oncotarget.2524
PII 2524
PMID 25301737
PMC PMC4279398
MeSH AC133 Antigen Animals Antigens, CD / genetics Antigens, CD / metabolism* Apoptosis Blotting, Western Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / mortality Carcinoma, Hepatocellular / pathology Cell Differentiation Cell Proliferation Chromatin Immunoprecipitation Female Flow Cytometry Fluorescent Antibody Technique Glycoproteins / genetics Glycoproteins / metabolism* Humans Ikaros Transcription Factor / genetics Ikaros Transcription Factor / metabolism* Immunoenzyme Techniques Immunoprecipitation Liver Neoplasms / metabolism* Liver Neoplasms / mortality Liver Neoplasms / pathology Male Mice Mice, Inbred BALB C Mice, Nude Middle Aged Neoplasm Grading Neoplasm Staging Neoplastic Stem Cells / metabolism* Neoplastic Stem Cells / pathology Peptides / genetics Peptides / metabolism* Prognosis RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Survival Rate Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 5.168
Human and Animal Cells HuH-7