Integrin [alpha]5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells

• Published in: Oncology letters 2021-07, Vol.22 (1), p.1
• Main Authors: Yang, Yang, Wang, Yizhe, Che, Xiaofang, Hou, Kezuo, Wu, Jie, Zheng, Chunlei, Cheng, Yang, Liu, Yunpeng, Hu, Xuejun, Zhang, Jingdong
• Format: Article
• Language: English
• Subjects: Aprotinin; Drug resistance; Ethylenediaminetetraacetic acid; Gene expression; Genetic aspects; Genetic research; Integrins; Lung cancer, Non-small cell; Lung cancer, Small cell; Tyrosine
• ISSN: 1792-1074
• DOI: 10.3892/ol.2021.12817

Patients with non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs) ultimately develop drug resistance and metastasis. Therefore, there is a need to identify the underlying mechanisms of resistance to EGFR-TKIs. In the present study, colony formation and MTT assays were performed to investigate cell viability following treatment with icotinib. Gene Expression Omnibus datasets were used to identify genes associated with resistance. Wound healing and Transwell assays were used to detect cell migration and invasion with icotinib treatment and integrin [alpha]5-knockdown. The expression levels of integrin [alpha]5 and downstream genes were detected using western blotting. Stable icotinib-resistant (IcoR) cell lines (827/IcoR and PC9/IcoR) were established that showed enhanced malignant properties compared with parental cells (HCC827 and PC9). Furthermore, the resistant cell lines were resistant to icotinib in terms of proliferation, migration and invasion. The enrichment of function and signaling pathways analysis showed that integrin [alpha]5-upregulation was associated with the development of icotinib resistance. The knockdown of integrin [alpha]5 attenuated the migration and invasion capability of the resistant cells. Moreover, a combination of icotinib and integrin [alpha]5 siRNA significantly inhibited migration and partly restored icotinib sensitivity in IcoR cells. The expression levels of phosphorylated (p)-focal adhesion kinase (FAK), p-STAT3 and p-AKT decreased after knockdown of integrin [alpha]5, suggesting that FAK/STAT3/AKT signaling had a notable effect on the resistant cells. The present study revealed that the integrin [alpha]5/FAK/STAT3/AKT signaling pathway promoted icotinib resistance and malignancy in IcoR NSCLC cells. This signaling pathway may provide promising targets against acquired resistance to EGFR-TKI in patients with NSCLC. Key words: icotinib resistance, integrin a5, migration, invasion, metastasis