Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma.
Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma.
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转录因子Ikaros对肝癌干细胞标志物CD133表达的抑制作用
DOI：
10.18632/oncotarget.2524
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Li JJ
中科院分区：
文献类型：
--
作者：
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
CD133是一种细胞表面糖蛋白，已被报道为肿瘤干细胞(CSCs)富集性的标志。然而，CD133的调控机制仍不清楚。CSCs被认为与辐射抵抗和多药耐药有关。CD133和CSCs关键调控因子的阐明对于CSC靶向治疗的发展至关重要。在这项研究中，我们发现Ikaros通过直接与CD133 P1启动子结合来抑制CD133的表达，并抑制CD133+肿瘤干细胞在肝细胞癌中的致瘤和自我更新能力。我们发现Ikaros作为转录抑制复合体与CtBP相互作用，抑制了CD133在肝细胞癌中的表达。我们还证明了ETS1上调了Ikaros的表达，而ETS1的活性受MAPKs途径的调节。此外，IkarosmRNA的表达降低与肝细胞癌患者的生存不良显著相关。总体而言，我们的研究确认Ikaros在肝细胞癌中发挥转录抑制因子的作用，是治疗肝细胞癌的新的重新激活的治疗靶点。同时，我们的发现提供了证据，表明Ikaros可能是靶基因CD133的一个有吸引力的抑制剂，CD133在靶向CSC治疗中重新激活抗癌机制。
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.
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