Department of Oral and Maxillofacial Surgery, University Medicine Göttingen, Göttingen, Germany.
Department of Oral and Maxillofacial Surgery, University Medicine Göttingen, Göttingen, Germany.
Int J Oral Maxillofac Surg. 2020 Feb;49(2):157-165. doi: 10.1016/j.ijom.2019.06.001. Epub 2019 Jul 23.
Tumour progression in head and neck squamous cell carcinoma (HNSCC) is influenced by the surrounding stroma and inflammatory cytokines such as tumour necrosis factor alpha (TNF-α). The aim of this study was to test the hypothesis that TNF-α modulates the interactions of HNSCC cell line PCI-13 and bone marrow mesenchymal stromal cells (BMSCs) and influences markers of epithelial-mesenchymal transition (EMT). Following induction with TNF-α, mono- and co-cultures of BMSCs and the established HNSCC cell line PCI-13 were analyzed; protein expression of E-cadherin and vimentin and qRT-PCR expression of Snail, Twist, MMP14, vimentin, E-cadherin, and β-catenin were examined, and changes in cellular AKT signalling were analyzed. TNF-α induced a significant decrease in E-cadherin (64.5±6.0%, P=0.002) and vimentin (10.4±3.5%, P=0.04) protein expression in co-cultured PCI-13, while qRT-PCR showed a significant increase in β-catenin (BMSCs P<0.0001; PCI-13 P=0.0005) and Snail (BMSCs P=0.009; PCI-13 P=0.01). TNF-α also resulted in a down-regulation of AKT downstream targets S6 (38.7±20.9%, P=0.01), p70S6 (16.7±12%, P=0.05), RSK1 (23.6±28.8%, P=0.02), and mTOR (27.4±17.5%, P=0.004) in BMSC co-cultures. In summary, while reducing the expression of vimentin and AKT-signalling in PCI-13 and BMSC, respectively, TNF-α introduced an inflammatory-driven tumour-stroma transition, marked by an increased expression of markers of EMT.
肿瘤在头颈部鳞状细胞癌（HNSCC）中的进展受到周围基质和炎症细胞因子（如肿瘤坏死因子α（TNF-α））的影响。本研究的目的是检验以下假设，即 TNF-α调节 HNSCC 细胞系 PCI-13 和骨髓间充质基质细胞（BMSC）之间的相互作用，并影响上皮-间充质转化（EMT）标志物的表达。在诱导 TNF-α后，分析了 BMSC 与已建立的 HNSCC 细胞系 PCI-13 的单培养物和共培养物；检测 E-钙黏蛋白和波形蛋白的蛋白表达，以及 Snail、Twist、MMP14、波形蛋白、E-钙黏蛋白和β-连环蛋白的 qRT-PCR 表达，并分析细胞 AKT 信号的变化。TNF-α诱导共培养的 PCI-13 中 E-钙黏蛋白（64.5±6.0%，P=0.002）和波形蛋白（10.4±3.5%，P=0.04）的蛋白表达显著降低，而 qRT-PCR 显示β-连环蛋白（BMSC P<0.0001；PCI-13 P=0.0005）和 Snail（BMSC P=0.009；PCI-13 P=0.01）的表达显著增加。TNF-α还导致 BMSC 共培养物中 AKT 下游靶标 S6（38.7±20.9%，P=0.01）、p70S6（16.7±12%，P=0.05）、RSK1（23.6±28.8%，P=0.02）和 mTOR（27.4±17.5%，P=0.004）的下调。总之，虽然 TNF-α降低了 PCI-13 和 BMSC 中波形蛋白和 AKT 信号的表达，但它引入了一种炎症驱动的肿瘤-基质转化，表现为 EMT 标志物表达增加。
