Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Surgery, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Medical Microbiology & Infectious Diseases, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Biochim Biophys Acta Mol Cell Res. 2018 May;1865(5):749-768. doi: 10.1016/j.bbamcr.2018.02.007. Epub 2018 Feb 24.
Lung cancer is considered one of the most frequent causes of cancer-related death worldwide and Non-Small Cell Lung Cancer (NSCLC) accounts for 80% of all lung cancer cases. Autophagy is a cellular process responsible for the recycling of damaged organelles and protein aggregates. Transforming growth factor beta-1 (TGFβ) is involved in Epithelial to Mesenchymal Transition (EMT) and autophagy induction in different cancer models and plays an important role in the pathogenesis of NSCLC. It is not clear how autophagy can regulate EMT in NSCLC cells. In the present study, we have investigated the regulatory role of autophagy in EMT induction in NSCLC and show that TGFβ can simultaneously induce both autophagy and EMT in the NSCL lines A549 and H1975. Upon chemical inhibition of autophagy using Bafilomycin-A1, the expression of the mesenchymal marker vimentin and N-cadherin was reduced. Immunoblotting and immunocytochemistry (ICC) showed that the mesenchymal marker vimentin was significantly downregulated upon TGFβ treatment in ATG7 knockdown cells when compared to corresponding cells treated with scramble shRNA (negative control), while E-cadherin was unchanged. Furthermore, autophagy inhibition (Bafilomycin A1 and ATG7 knockdown) decreased two important mesenchymal functions, migration and contraction, of NSCLC cells upon TGFβ treatment. This study identified a crucial role of autophagy as a potential positive regulator of TGFβ-induced EMT in NSCLC cells and identifies inhibitors of autophagy as promising new drugs in antagonizing the role of EMT inducers, like TGFβ, in the clinical progression of NSCLC.
肺癌被认为是全球癌症相关死亡的最常见原因之一，而非小细胞肺癌（NSCLC）占所有肺癌病例的 80%。自噬是一种负责回收受损细胞器和蛋白聚集体的细胞过程。转化生长因子β-1（TGFβ）参与不同癌症模型中的上皮间质转化（EMT）和自噬诱导，在 NSCLC 的发病机制中起着重要作用。目前尚不清楚自噬如何调节 NSCLC 细胞中的 EMT。在本研究中，我们研究了自噬在 NSCLC 中 EMT 诱导中的调节作用，结果表明 TGFβ可同时诱导 A549 和 H1975 两种 NSCLC 细胞系中的自噬和 EMT。用 Bafilomycin-A1 化学抑制自噬后，间充质标志物波形蛋白和 N-钙粘蛋白的表达减少。免疫印迹和免疫细胞化学（ICC）显示，与用 scramble shRNA（阴性对照）处理的相应细胞相比，在 ATG7 敲低细胞中，TGFβ 处理后间充质标志物波形蛋白的表达明显下调，而 E-钙粘蛋白不变。此外，自噬抑制（Bafilomycin A1 和 ATG7 敲低）降低了 TGFβ处理后 NSCLC 细胞的两种重要的间质功能，即迁移和收缩。本研究确定了自噬作为 TGFβ诱导的 NSCLC 细胞 EMT 的潜在正调节剂的关键作用，并确定自噬抑制剂作为有前途的新型药物，可拮抗 EMT 诱导剂（如 TGFβ）在 NSCLC 临床进展中的作用。
