Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer.
Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer.
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DOI：
10.1016/j.neo.2015.07.001
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Chellappan S
中科院分区：
文献类型：
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作者：
Bora-Singhal N;Perumal D;Nguyen J;Chellappan S
非小细胞肺癌（NSCLC）患者的生存率非常低，因为目前的治疗策略并不完全有效。尽管EGFR酪氨酸激酶抑制剂对携带EGFR突变的NSCLC患者有效，但患者总是对这些药物产生耐药性。多个信号级联的改变与EGFR抑制剂耐药性的发展相关。Sonic Hedgehog和相关的Gli转录因子在胚胎发育中起重要作用，最近发现在NSCLC中重新激活，Gli1水平升高与预后不良相关。Hedgehog通路与癌症干细胞的功能有关，尽管其潜在的分子机制尚不清楚。在这种情况下，我们证明，Gli1是一个强大的调节胚胎干细胞转录因子Sox 2。Gli1的耗尽或Hedgehog信号的抑制显著地废除了来自NSCLC的干细胞样侧群细胞的自我更新以及这些细胞的血管拟态。发现Gli1通过其启动子区域转录调节Sox 2，并且Gli1可以在Sox 2启动子上检测到。Hedgehog信号传导的抑制似乎与EGFR抑制剂协同作用，显著降低NSCLC细胞的活力以及干细胞样细胞的自我更新。因此，我们的研究证明了EGFR信号传导和Hedgehog通路在控制NSCLC癌症干细胞的干细胞样功能中的协同作用，并提出了一种新的治疗策略来对抗携带EGFR突变的NSCLC。
Non–small cell lung cancer (NSCLC) patients have very low survival rates because the current therapeutic strategies are not fully effective. Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents. Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors. Sonic Hedgehog and associated Gli transcription factors play a major role in embryonic development and have recently been found to be reactivated in NSCLC, and elevated Gli1 levels correlate with poor prognosis. The Hedgehog pathway has been implicated in the functions of cancer stem cells, although the underlying molecular mechanisms are not clear. In this context, we demonstrate that Gli1 is a strong regulator of embryonic stem cell transcription factor Sox2. Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells. Gli1 was found to transcriptionally regulate Sox2 through its promoter region, and Gli1 could be detected on the Sox2 promoter. Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells. Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.