School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Cancer Res. 2011 May 1;71(9):3410-21. doi: 10.1158/0008-5472.CAN-10-3340.
Glioma stem cells (GSC) possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Thus, they are considered to be major drivers for glioma initiation, progression, and recurrence. However, the precise mechanism governing acquisition of their drug resistance remains to be elucidated. Our previous study has shown that inhibitor of differentiation 4 (ID4) dedifferentiates Ink4a/Arf(-/-) mouse astrocytes and human glioma cells to glioma stem-like cells (induced GSCs or iGSCs). In this article, we report that ID4-driven iGSCs exhibit chemoresistant behavior to anticancer drugs through activation of ATP-binding cassette (ABC) transporters. We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region. Consequently, ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. Furthermore, we found that short hairpin RNA-mediated knockdown of SOX2 in ID4-driven iGSCs resulted in loss of cancer stemness. Moreover, ectopic expression of SOX2 could dedifferentiate Ink4a/Arf(-/-) astrocytes and glioma cells to iGSCs, indicating a crucial role of SOX2 in genesis and maintenance of GSCs. Finally, we found that the significance of the ID4-miR-9*-SOX2-ABCC3/ABCC6 regulatory pathway is recapitulated in GSCs derived from patients with glioma. Together, our results reveal a novel regulatory mechanism by which ID4-driven suppression of miR-9* induces SOX2, which imparts stemness potential and chemoresistance to glioma cells and GSCs.
神经胶质瘤干细胞（GSC）具有肿瘤起始潜能，对常规化疗和放疗具有相对抗性。因此，它们被认为是神经胶质瘤起始、进展和复发的主要驱动因素。然而，调控其获得耐药性的确切机制仍有待阐明。我们之前的研究表明，分化抑制因子 4（ID4）可将 Ink4a/Arf(-/-) 小鼠星形胶质细胞和人神经胶质瘤细胞分化为神经胶质瘤干细胞样细胞（诱导的 GSC 或 iGSC）。在本文中，我们报告 ID4 驱动的 iGSC 通过激活三磷酸腺苷结合盒（ABC）转运体表现出对抗癌药物的耐药行为。我们发现 ID4 通过抑制 microRNA-9*（miR-9*）来增强 SOX2 蛋白的表达，miR-9* 通过靶向其 3'-非翻译区来抑制 SOX2。因此，ID4 介导的 SOX2 诱导通过直接转录调控增强 ABCC3 和 ABCC6 的表达，表明 ID4 通过促进 SOX2 介导的 ABC 转运体诱导来调节 iGSC 的耐药性。此外，我们发现 ID4 驱动的 iGSC 中短发夹 RNA 介导的 SOX2 敲低导致癌症干性丧失。此外，SOX2 的异位表达可将 Ink4a/Arf(-/-) 星形胶质细胞和神经胶质瘤细胞分化为 iGSC，表明 SOX2 在 GSC 的发生和维持中起关键作用。最后，我们发现 ID4-miR-9*-SOX2-ABCC3/ABCC6 调控途径在源自神经胶质瘤患者的 GSC 中得到了重现。总之，我们的研究结果揭示了一种新的调控机制，即 ID4 驱动的 miR-9*抑制诱导 SOX2，赋予神经胶质瘤细胞和 GSC 干细胞特性和耐药性。
