Decreased human antigen R expression confers resistance to tyrosinekinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibitingBim expression

作者：Yunfeng Yao; Huili Chu; Jun Wang; Baocheng Wang

来源：International Journal of Molecular Medicine, 2018, 42(5).

DOI：10.3892/ijmm.2018.3835

• Wernicke脑病
• 直肠癌
• 重症护理 Wernicke encephalopathy
• Rectal cancer
• Critical care

Primary resistance to epidermal growth factor receptor?tyrosine kinase inhibitors(EGFR?TKIs) is an obstacle for the treatment of non?small cell lung cancer (NSCLC);however, the associated mechanisms are not well understood. Studies have reportedthat Bim expression levels may be associated with the efficacy of EGFR?TKI treatmentin NSCLC patients harboring EGFR mutations. Human antigen R (HuR) regulates themRNA and protein expression of target genes, including certain B?cell lymphoma 2family members. The present study investigated whether HuR mediates resistanceto EGFR?TKIs via the regulation of Bim. The results demonstrated that decreasedlevels of HuR and Bim protein expression are associated with primary resistanceto EGFR?TKIs and reduced median progression?free survival in NSCLC patients. In vitroassays also revealed that knockdown of HuR resulted in primary EGFR?TKI resistanceand reduced gefitinib?induced apoptosis in HCC827 cells by decreasing Bim expression.Furthermore, elevated HuR expression restored gefitinib sensitivity and enhancedgefitinib?induced apoptosis in H1650 cells by increasing Bim expression. In vivo,it was further demonstrated that overexpression of HuR was able to restore thegefitinib sensitivity of H1650 cells. Therefore, altered HuR/Bim expression isproposed to be a novel mechanism of EGFR?TKI resistance in NSCLC.

• 出版日期2018
• 单位中国人民解放军第二军医大学