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

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.

CD133是一种细胞表面糖蛋白，据报道它是富集癌症干细胞（CSCs）的标志物。然而，CD133的调控机制仍然未知。癌症干细胞被认为与放射抗性和多药耐药性有关。阐明CD133和癌症干细胞的关键调控因子对于开发针对癌症干细胞的疗法至关重要。在这项研究中，我们发现Ikaros通过直接结合到CD133 P1启动子抑制CD133的表达，并抑制肝细胞癌（HCC）中CD133⁺癌症干细胞样细胞的致瘤性和自我更新能力。我们发现Ikaros作为一种转录抑制复合物与CtBP相互作用，从而抑制肝细胞癌中CD133的表达。我们还证明Ikaros的表达受ETS1上调，而ETS1的活性受MAPKs通路调控。此外，Ikaros表达降低与肝细胞癌患者的不良生存显著相关。总体而言，我们的研究确定Ikaros在肝细胞癌中作为一种转录抑制因子发挥作用，并且是治疗肝细胞癌的一个新的重新激活的治疗靶点。同时，我们的研究结果提供了证据，表明Ikaros可能是靶基因CD133的一种有吸引力的抑制剂，它在针对癌症干细胞的治疗中重新激活抗癌机制。