6号乘客
基因敲除
PI3K/AKT/mTOR通路
癌症研究
下调和上调
蛋白激酶B
上皮-间质转换
生物
LY294002型
转移
顺铂
细胞迁移
肺癌
转录因子
化学
细胞生物学
信号转导
细胞
癌症
病理
医学
细胞培养
基因
生物化学
化疗
遗传学
作者
Dongming Wu,Ting Zhang,Yabin Liu,Shi‐hua Deng,Rong Han,Teng Li,Jing Li,Ying Xu
标识
DOI:10.1038/s41419-019-1591-4
摘要
Abstract Paired-box 6 (PAX6) is an important transcription factor required for the function of human neuroectodermal epithelial tissues. Previous studies have suggested that it is also expressed in several types of tumors and has an oncogenic role. However, little is known about its role in non-small cell lung cancer (NSCLC). Here, we found that PAX6 expression levels were upregulated in human lung cancer tissues and correlated with poor clinical outcomes. PAX6 overexpression significantly promoted NSCLC epithelial-to-mesenchymal transition (EMT) and metastasis, whereas its knockdown inhibited these processes. PAX6 is commonly correlated with EMT-mediated stem cell transformation, thereby inducing cisplatin resistance. Using the RT 2 Profiler PCR Array, we found that WNT5A , EGFR , and ZEB2 were differentially regulated in response to PAX6 modulation. In addition, PAX6 directly bound to the promoter region of ZEB2 . ZEB2 knockdown significantly reduced the expression and function of PAX6. ZEB2 was upregulated upon PAX6 overexpression and downregulated upon PAX6 knockdown, whereas E-cadherin expression negatively correlated with PAX6 levels. Moreover, p-PI3K and p-AKT were significantly enhanced by PAX6, which was reversed by the addition of the PI3K-AKT inhibitor, LY294002. These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2 , thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients.
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