Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, 901 Chung-Hwa Road, Tainan, 71004, Taiwan.
Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan.
BMC Cancer. 2019 Aug 9;19(1):791. doi: 10.1186/s12885-019-6014-5.
Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. However, the role of Egr1 in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways.
Egr1, osteopontin (OPN) and Oct4 expression in human lung cancer was determined by performing immunohistochemistry. Immunoblotting, ELISA, luciferase reporter assay, chromatin immunoprecipitation assay and RT-PCR were performed to validate the regulation of Oct4-Egr1-OPN axis. Moreover, the effect of Oct4-Egr1-OPN axis on lung cancer progression was evaluated by cell migration assay and mice study.
We detected Oct4, Egr1, and OPN expression in clinical specimens from 79 lung cancer patients, including 72 adenocarcinomas and 7 squamous cell carcinomas. High expression of Oct4, Egr1, and OPN accounted for 53, 51, and 57% of the patients, respectively. All of the three biomarkers were positively correlated in clinical human lung cancer. Patients with high expression of OPN were significantly associated with shorter disease-free survivals than those with low expression of OPN (p < 0.05). In lung cancer cells, Oct4 transactivated the Egr1 promoter and upregulated Egr1 expression. In a human lung cancer xenograft model, Oct4-overexpressing tumors expressed elevated levels of Egr1. Furthermore, overexpression of Oct4 in lung cancer cells increased the metastatic potential.
Egr1 exerts a promoting effect on cancer metastasis in Oct4-overexpressing lung cancer. Thus, therapeutic strategies targeting the Oct4/Egr1/OPN axis may be further explored for the treatment of lung cancer, especially when lung cancer is refractory to conventional treatment due to cancer stem cells.
在肺癌中，癌症干细胞和早期生长反应基因 1（Egr1）的作用已经得到了广泛的研究。然而，Egr1 在肺癌转移中的作用仍不确定，特别是在与干细胞相关的途径方面。
通过免疫组织化学检测人肺癌中 Egr1、骨桥蛋白（OPN）和 Oct4 的表达。通过免疫印迹、ELISA、荧光素酶报告基因检测、染色质免疫沉淀检测和 RT-PCR 验证 Oct4-Egr1-OPN 轴的调节。此外，通过细胞迁移实验和小鼠研究评估 Oct4-Egr1-OPN 轴对肺癌进展的影响。
我们检测了 79 例肺癌患者的临床标本中 Oct4、Egr1 和 OPN 的表达，包括 72 例腺癌和 7 例鳞状细胞癌。Oct4、Egr1 和 OPN 的高表达分别占患者的 53%、51%和 57%。在临床人肺癌中，这三种生物标志物均呈正相关。OPN 高表达的患者与 OPN 低表达的患者相比，无病生存率明显缩短（p<0.05）。在肺癌细胞中，Oct4 转录激活 Egr1 启动子并上调 Egr1 表达。在人肺癌异种移植模型中，Oct4 过表达的肿瘤表达了更高水平的 Egr1。此外，肺癌细胞中 Oct4 的过表达增加了转移潜能。
Egr1 在 Oct4 过表达的肺癌中对癌症转移发挥促进作用。因此，针对 Oct4/Egr1/OPN 轴的治疗策略可能进一步被探索用于治疗肺癌，特别是当肺癌由于癌症干细胞而对常规治疗产生抗性时。
