Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells

Yang Yang; Yizhe Wang; Xiaofang Che; Kezuo Hou; Jie Wu; Chunlei Zheng; Yang Cheng; Yunpeng Liu; Xuejun Hu; Jingdong Zhang

doi:10.3892/ol.2021.12817

Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells

Oncol Lett. 2021 Jul;22(1):556. doi: 10.3892/ol.2021.12817. Epub 2021 May 24.

Authors

Yang Yang¹, Yizhe Wang¹, Xiaofang Che^{2

3}, Kezuo Hou^{2

3}, Jie Wu¹, Chunlei Zheng^{2

3}, Yang Cheng¹, Yunpeng Liu^{2

3}, Xuejun Hu¹, Jingdong Zhang²

Affiliations

¹ Department of Respiratory and Infectious Disease of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
² Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
³ Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.

Abstract

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 α5-knockdown. The expression levels of integrin α5 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 α5-upregulation was associated with the development of icotinib resistance. The knockdown of integrin α5 attenuated the migration and invasion capability of the resistant cells. Moreover, a combination of icotinib and integrin α5 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 α5, suggesting that FAK/STAT3/AKT signaling had a notable effect on the resistant cells. The present study revealed that the integrin α5/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.

Keywords: icotinib resistance; integrin α5; invasion; metastasis; migration.

Grants and funding

The study was funded by The National Key Research and Development Program of China (grant no. 2017YF1309403), The National Natural Science Foundation of China (grant nos. 81972197 and 81472193), The Key Research and Development Program of Liaoning Province (grant no. 2018225060), The Natural Science Foundation of Liaoning Province (grant no. 2019-ZD-777), The Technological Special Project of Liaoning Province of China (grant no. 2019020176-JH1/103), The Science and Technology Plan Project of Liaoning Province (grant no. 2013225585) and Science and Technology Plan Project of Shenyang City (grant no. 19-112-4-099).