Clinical Laboratory, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, China.
Cell Death Dis. 2019 Apr 25;10(5):349. doi: 10.1038/s41419-019-1591-4.
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 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.
配对盒基因 6（PAX6）是人类神经外胚层上皮组织功能所必需的重要转录因子。先前的研究表明，它也在几种类型的肿瘤中表达，并具有致癌作用。然而，关于它在非小细胞肺癌（NSCLC）中的作用知之甚少。在这里，我们发现 PAX6 在人类肺癌组织中的表达水平上调，并与不良的临床结局相关。PAX6 过表达显著促进 NSCLC 上皮间质转化（EMT）和转移，而其敲低则抑制这些过程。PAX6 通常与 EMT 介导的干细胞转化相关，从而诱导顺铂耐药。使用 RT Profiler PCR 阵列，我们发现 WNT5A、EGFR 和 ZEB2 对 PAX6 调节的反应存在差异调节。此外，PAX6 直接与 ZEB2 启动子区域结合。ZEB2 敲低显著降低了 PAX6 的表达和功能。PAX6 过表达上调 ZEB2，而 PAX6 敲低下调 ZEB2，而 E-钙粘蛋白表达与 PAX6 水平呈负相关。此外，p-PI3K 和 p-AKT 被 PAX6 显著增强，PI3K-AKT 抑制剂 LY294002 的加入可逆转这一增强。这些数据表明，PAX6 可以通过直接结合 ZEB2 的启动子区域，通过 PI3K/AKT 信号通路介导 E-钙粘蛋白下调，从而介导细胞迁移、干细胞转化和顺铂耐药；最终影响 NSCLC 患者的生存。
