RESUMEN
This study aimed to map the hub genes and potential pathways that might be involved in the molecular pathogenesis of EGFR-TKI resistance in NSCLC. We performed bioinformatics analysis to identify differentially expressed genes, their function, gene interactions, and pathway analysis between EGFR-TKI-sensitive and EGFR-TKI-resistant patient-derived xenotransplantation samples based on Gene Expression Omnibus database. Survival analysis was performed via the GEPIA database (GEO). The relationship between the key gene ITGAM and the therapeutic candidates was retrieved from DGIdb. A total of 1,302 differentially expressed genes were identified based on GEO. The PPI network highlighted 10 potential hub genes. Only ITGAM was linked to poor DSF in NSCLC patients. A total of 10 drugs were predicted to be potential therapeutics for NSCLC with EGFR-TKI resistance. This study indicates the hub genes related to EGFR-TKI resistance in NSCLC through bioinformatics technologies which can improve the understanding of the mechanisms of EGFR-TKI resistance and provide novel insights into therapeutics.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , BiomarcadoresRESUMEN
Sufentanil, a commonly used opioid analgesic, could mimic ischemia postconditioning to attenuate ischemia reperfusion injury, but this effect might be hindered in diabetic animals by inhibition of glycogen synthase kinase-3ß phosphorylation. Also, diabetes can abrogate the cardioprotection of sevoflurane (an inhaled anesthetic) against ischemia reperfusion injury, and short-term insulin treatment does not restore protection by sevoflurane postconditioning. We hypothesized that long-term insulin treatment might restore the cardioprotective effect of sufentanil postconditioning in diabetic rats via phosphorylation of glycogen synthase kinase-3ß. Streptozotocin (55 mg/kg)-induced diabetic rats received insulin (Novolin N, 6-8 u/d) for two days or two weeks, then were exposed to 30-min ischemia and 120-min reperfusion. Sufentanil postconditioning was performed 5 min before the onset of reperfusion. Controls included non-diabetic rats, sham surgery for ischemia/reperfusion, and sufentanil vehicle. Infarct size, cardiac troponin I, and phosphorylated glycogen synthase kinase-3ß were examined. Sufentanil postconditioning reduced infarct size by 46% in non-diabetic rats (P < 0.001), but diabetes prevented this protective effect. Two-day insulin treatment was not effective, but two-week treatment reduced infarct size by 45% (P < 0.001), reduced cardiac troponin I by 33% (P < 0.001), and increased phosphorylated glycogen synthase kinase-3ß levels (P < 0.001) in the diabetic sufentanil postconditioning group. In conclusion, sufentanil-induced cardioprotection was restored by long-term insulin treatment. The underlying mechanism may be increased phosphorylation of glycogen synthase kinase-3ß.
