ABSTRACT
BACKGROUND@#Lung cancer is the malignant tumor with the highest incidence and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for about 80%. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapy has been playing an important role in treatment of NSCLC. However, unavoidable therapeutic resistance significantly limits the clinical efficacy of EGFR-TKI. As a key member of the forkhead box protein family, FOXC1 is aberrantly expressed in NSCLC and involved in NSCLC progression. The aim of this work is to investigate the effect and potential mechanism of FOXC1 on gefitinib resistance in NSCLC.@*METHODS@#Western blot was performed to assess the expression of FOXC1 protein in HCC827/GR cells. Immunohistochemistry (IHC) assays were performed in human NSCLC tissues with gefitinib resistance. HCC827/GR cells were transfected with shRNA specifically targeting FOXC1 mRNA and stable cell lines were established. The effects of FOXC1 on cell viability and apoptosis were analyzed using a new methyl thiazolyl tetrazolium assay (MTS assay) and flow cytometry. Self-renewal ability was determined by mammosphere-formation analysis. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to detect the expression of SOX2, Nanog, OCT4 and CD133. Flow cytometry analysis were further used to detect the level of CD133. IHC assays were used to detect the levels of SOX2 and CD133 in NSCLC tissues with genfitiinb resistance. Correlations of the expressions of FOXC1, CD133 and SOX2 with each other in lung adenocarcinoma samples were analyzed based on The Cancer Genome Atlas (TCGA) database.@*RESULTS@#The expression of FOXC1 is significantly increased in HCC827/GR cells compared with HCC827 cells (P<0.05). IHC results showed FOXC1 was highly expressed in NSCLC tissues with gefitinib resisitance. Knockdown of FOXC1 significantly increased the sensitivity of HCC827/GR cells to gefitinib. The cell viability was decreased and the apoptosis was promoted (P<0.05). Moreover, FOXC1 knockdown apparently inhibited the expression of SOX2 and CD133, and decreased the mammosphere-formation capacity in HCC827/GR cells. In NSCLC tissues with gefitinib resistance, the expressions of SOX2 and CD133 were significantly higher compared with gefitinib-sensitive tissues (P<0.01). Meanwhile, the expressions of FOXC1, CD133 and SOX2 with each other were positively correlated (P<0.05).@*CONCLUSIONS@#FOXC1 could increase gefitinib resitance in NSCLC, by which mechanism is related to the regulation of cancer stem cell properties.
ABSTRACT
Objective:To analyze the clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced NSCLC.Methods:We collected 23 cases of NSCLC advanced patients, who were treated in the affiliated Cancer Hospital of Guangzhou Medical University from January 2015 to March 2020. And these 23 cases of patients with first-generation EGFR-TKIs resistance were treated with the third-generation EGFR-TKI drugs. We analyzed their clinicopathological characteristics, studied their therapeutic effects, and followed up their progression-free survival (PFS).Results:It is showed that 16 of 23 cases (69.56%) were got local progression and 7 of 23 cases (31.43%) were found with systemic progression. Briefly, the median PFS of the 23 patients was 17.5 months. A total of 7 cases occurred rashes after taking EGFR-TKI, and 3 cases got abnormal liver function. Fortunately, they were all improved after symptomatic treatments. Additionally, no bone marrow suppression (granulocytes, neutropenia, thrombocytopenia, anemia) and digestive tract reactions (nausea, vomiting, diarrhea) were occurred in 23 cases of NSCLC patients. The mental and physical improvement of EGFR-TKI in the third generation of 19 patients was more obvious than that in the first generation of EGFR-TKI. Among them, 15 cases showed more obvious lesion shrinkage after third-generation EGFR-TKI treatment. 4 patients with GGO had cleaner disappearance than that of the first-generation EGFR-TKI.Conclusions:Compared with traditional chemotherapy, the first-generation EGFR-TKI resistance treatment with three-generation EGFR-TKI treatment has better efficacy with reduced toxic and side effects, and significantly improved the life quality of advanced NSCLC patients.