Department of Biochemistry, School of Medicine, Jeju National University, Jeju 690-756, Korea.
Institute of Medical Science, Jeju National University, Jeju 690-756, Korea.
Cells. 2020 Jun 26;9(6):1555. doi: 10.3390/cells9061555.
Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in tumorigenesis and organ fibrosis. Growth factors such as epidermal growth factor and fibroblast growth factor in addition to cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of cancer progression such as invasion, metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms-NOX2 and NOX4-that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the focal adhesion kinase (FAK)/SRC pathway in HeLa, human cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of cytokine mediated EMT and its associated processes via tyrosine phosphorylation of the FAK/SRC pathway.
上皮间质转化 (EMT) 在肿瘤发生和器官纤维化中促进了上皮细胞相关的疾病特征。表皮生长因子和成纤维细胞生长因子等生长因子以及转化生长因子-β1 (TGF-β1) 等细胞因子据说在癌症进展的相关病理事件的重塑中发挥着突出作用，如侵袭、转移、凋亡、EMT 等，通过与氧化还原相关的细胞二级信使，特别是活性氧 (ROS)。然而，氧化还原机制以及 EMT 进展背后的信号级联仍知之甚少。在这项研究中，在 TGF-β1 处理后，我们观察到 NOX 同工型-NOX2 和 NOX4 的诱导，它们具有时间（早期和晚期）和细胞定位（核和自噬体共定位）依赖性效应，通过在 HeLa 细胞中激活粘着斑激酶 (FAK)/Src 途径来介导 EMT 相关的细胞增殖和迁移，人宫颈癌细胞。沉默 NOX2/4 基因表达并使用 Src 抑制剂 (AZD0530) 后，TGF-β1 诱导的 EMT 相关细胞重塑、细胞外基质 (ECM) 产生、细胞迁移和侵袭的进展明显逆转。总之，这些结果表明，NOX2 和 NOX4 通过 FAK/Src 途径的酪氨酸磷酸化在细胞因子介导的 EMT 及其相关过程的激活中发挥重要作用，尽管作用不同。
