Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China.
School of Life Sciences and Biopharmaceutical Sciences, Shenyang Pharmaceutical University, Liaoning 110016, People's Republic of China.
Biomed Pharmacother. 2020 Jul;127:110225. doi: 10.1016/j.biopha.2020.110225. Epub 2020 May 16.
Cancer drug resistance and epithelial-mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, have recently been associated with the existence of cancer stem cells (CSCs). However, there are no appropriate CSC-markers of non-small cell lung cancer (NSCLC)-associated drug resistance and EMT. It is unknown if and how the drug-resistant and EMT phenotypes in NSCLC cells link to specific stemness-related pathways. Here, we found a significant elevated expression of both Oct4 and Nanog in gefitinib-resistant NSCLC cells, which displayed multi-drug resistance (MDR) properties and exhibited EMT phenotype. Ectopic co-expression of Oct4/Nanog empowered NSCLC cells with cancer stem cell properties, including self-renewal, drug resistance, EMT and high tumorigenic capacity. Following molecular mechanism investigation indicated Oct4/Nanog-regulated drug resistance and EMT change through Wnt/β-catenin signaling activation. Moreover, silencing β-catenin abrogated Oct4/Nanog-mediated MDR and EMT process in NSCLC cells. Our findings propose Wnt/β-catenin pathway as a promising therapeutic target for the treatment of progression and metastasis of NSCLC with CSC-like signatures and epithelial-mesenchymal transition phenotype.
癌症耐药性和上皮-间充质转化（EMT），是癌症侵袭和转移的关键过程，最近与癌症干细胞（CSC）的存在有关。然而，目前还没有非小细胞肺癌（NSCLC）相关耐药性和 EMT 的合适 CSC 标志物。目前尚不清楚 NSCLC 细胞中的耐药性和 EMT 表型是否以及如何与特定的干性相关途径相关。在这里，我们发现 gefitinib 耐药的 NSCLC 细胞中 Oct4 和 Nanog 的表达显著上调，这些细胞表现出多药耐药（MDR）特性，并表现出 EMT 表型。Oct4/Nanog 的异位共表达赋予 NSCLC 细胞具有癌症干细胞特性，包括自我更新、耐药性、EMT 和高致瘤能力。随后的分子机制研究表明，Oct4/Nanog 通过 Wnt/β-catenin 信号通路激活来调节耐药性和 EMT 变化。此外，沉默 β-catenin 可阻断 NSCLC 细胞中 Oct4/Nanog 介导的 MDR 和 EMT 过程。我们的研究结果表明，Wnt/β-catenin 通路是治疗具有 CSC 样特征和上皮-间充质转化表型的 NSCLC 进展和转移的有前途的治疗靶点。
