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

// Lin Zhang 1,* , Hong Li 1,* , Chao Ge 1 , Meng Li 1 , Fang-yu Zhao 1 , He-lei Hou 1 , Miao-xin Zhu 1 , Hua Tian 1 , Li-xing Zhang 1 , Tao-yang Chen 2 , Guo-ping Jiang 3 , Hai-yang Xie 3 , Ying Cui 4 , Ming Yao 1 and Jin-jun Li 1 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Qi Dong Liver Cancer Institute, Qi Dong, China 3 Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 4 Cancer Institute of Guangxi, Nanning, China * These authors contributed equally to this work Correspondence: Jin-jun Li, email: // Keywords : Ikaros; CD133; hepatocellular carcinoma; cancer stem cells Received : August 01, 2014 Accepted : September 24, 2014 Published : September 25, 2014 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.