Non-small cell lung cancer (NSCLC) is a prevalent tumor and acidic tumor microenvironment provides an energy source driving tumor progression. We previously demonstrated significantly upregulated Integrin β6 (ITGB6) in NSCLC cells. This study was designed to investigate the role of ITGB6 in NSCLC metastasis and explore the potential mechanisms. The expression of ITGB6 was evaluated in patients with NSCLC. Migration and invasion assays were utilized to investigate the role of ITGB6, and ChIP-qPCR and dual-luciferase reporter experiments preliminarily analyzed the relationship between ETS proto-oncogene 1 (ETS1) and ITGB6. Bioinformatics analysis and rescue models were performed to explore the underlying mechanisms. The results demonstrated that ITGB6 was upregulated in NSCLC patients and the difference was even more pronounced in patients with poor prognosis. Functionally, acidity-induced ITGB6 promoted migration and invasion of NSCLC cells in vitro, and epithelial-mesenchymal transition (EMT) and focal adhesion were the important mechanisms responsible for ITGB6-involved metastasis. Mechanistically, we revealed ETS1 enriched in the ITGB6 promoter region and promoted transcription to triggered the activation of subsequent signaling pathways. Moreover, ChIP-qPCR and dual-luciferase reporter experiments demonstrated that ETS1 played an important role in directly mediating ITGB6 expression. Furthermore, we found ITGB6 was responsible for the acidic microenvironment-mediated migration and invasion processes in NSCLC by performing rescue experiments with ITGB6 knockdown. Our findings indicated acidic microenvironment directly induced ETS1 to regulate the expression of ITGB6, and then the highly expressed ITGB6 further mediate EMT and activates the downstream focal adhesion pathways, eventually promotes the invasion and migration in NSCLC progression and metastasis.

中文翻译：

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酸性诱导的ITGB6通过上皮间质转化和粘着斑促进肺癌细胞的迁移和侵袭

非小细胞肺癌（NSCLC）是一种常见的肿瘤，酸性肿瘤微环境提供了驱动肿瘤进展的能量来源。我们之前证明 NSCLC 细胞中整合素 β6 (ITGB6) 显着上调。本研究旨在探讨ITGB6在NSCLC转移中的作用并探讨其潜在机制。评估了 NSCLC 患者中 ITGB6 的表达。采用迁移和侵袭实验研究ITGB6的作用，并通过ChIP-qPCR和双荧光素酶报告基因实验初步分析ETS原癌基因1（ETS1）与ITGB6之间的关系。进行生物信息学分析和救援模型以探索潜在机制。结果表明，ITGB6在NSCLC患者中表达上调，并且这种差异在预后不良的患者中更为明显。从功能上讲，酸性诱导的ITGB6在体外促进NSCLC细胞的迁移和侵袭，上皮间质转化（EMT）和粘着斑是ITGB6相关转移的重要机制。从机制上讲，我们揭示了 ETS1 在 ITGB6 启动子区域富集并促进转录，从而触发后续信号通路的激活。此外，ChIP-qPCR和双荧光素酶报告基因实验表明ETS1在直接介导ITGB6表达中发挥重要作用。此外，我们通过敲低 ITGB6 进行救援实验，发现 ITGB6 负责 NSCLC 中酸性微环境介导的迁移和侵袭过程。我们的研究结果表明，酸性微环境直接诱导ETS1调节ITGB6的表达，然后高表达的ITGB6进一步介导EMT并激活下游粘着斑通路，最终促进NSCLC进展和转移的侵袭和迁移。