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Background. Gefitinib resistance remains a major problem in the treatment of lung cancer. However, the underlying mechanisms involved in gefitinib resistance are largely unclear. Methods. Open-accessed data of lung cancer patients were downloaded from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. CCK8, colony formation, and 5-ethynyl-2′-deoxyuridine assays were utilized to evaluate the cell proliferation ability. Transwell and wound-healing assays were utilized to evaluate the cell invasion and migration ability. Quantitative real-time PCR was utilized to detect the RNA level of specific genes. Results. Here, we obtained the expression profile data of wild and gefitinib-resistant cells. Combined with the data from the TCGA and GDSC databases, we identified six genes, RNF150, FAT3, ANKRD33, AFF3, CDH2, and BEX1, that were involved in gefitinib resistance in both cell and tissue levels. We found that most of these genes were expressed in the fibroblast of the NSCLC microenvironment. Hence, we also comprehensively investigated the role of fibroblast in the NSCLC microenvironment, including its biological effect and cell interaction. Ultimately, CDH2 was selected for further analysis for its prognosis correlation. In vitro experiments presented the cancer-promoting role of CDH2 in NSCLC. Moreover, cell viability detection showed that the inhibition of CDH2 could significantly decrease the IC50 of gefitinib in NSCLC cells. GSEA showed that CDH2 could significantly affect the pathway activity of PI3K/AKT/mTOR signaling. Conclusions. This study is aimed at investigating the underlying mechanism involved in gefitinib resistance to lung cancer. Our research has improved researchers’ understanding of gefitinib resistance. Meanwhile, we found that CDH2 could lead to gefitinib resistance through PI3K/AKT/mTOR signaling. |
