中国病理生理杂志2025，Vol.41Issue(5)：871-881,11.DOI:10.3969/j.issn.1000-4718.2025.00.013
BCCIP通过调节DNA损伤修复途径增强胃癌对顺铂的耐药性
BCCIP promotes resistance of gastric cancer to cisplatin by modulating DNA damage repair pathways
摘要
Abstract
AIM:To investigate the role of BRCA2 and CDKN1A interacting protein(BCCIP)in gastric can-cer(GC)and elucidate its mechanism in mediating cisplatin resistance.METHODS:The BCCIP mRNA expression was assessed in GC tissues(n=415)and normal tissues(n=34)using The Cancer Genome Atlas(TCGA)database.In an in-ternal cohort(n=36 for RT-qPCR;n=5 for Western blot;n=30 for immunohistochemistry),BCCIP expression at both mRNA and protein levels was examined in GC tissues and paired adjacent normal tissues.Human GC cell lines AGS and HGC27 were cultured in vitro and treated with cisplatin in a dose(0,2,4,6,8 and 10 μmol/L)-and time(0,6,24 and 48 h)-dependent manner,followed by Western blot analysis of BCCIP expression.Stable BCCIP knockdown cell lines(shRNA#1 and shRNA#2 groups)were generated via lentiviral transfection,with empty vector-transfected cells serving as controls(vector group).Flow cytometry and colony formation assay were performed to evaluate the effects of BCCIP on apoptosis and colony-forming ability of GC cells treated with cisplatin.Western blot was utilized to detect the changes of BCCIP protein expression levels in the cytoplasm and nucleus of GC cells after cisplatin(2.5 and 1.0 μmol/L)treatment,as well as the effects of BCCIP on the expression of DNA damage marker γ-H2AX and apoptosis-related proteins cleaved caspase-9 and cleaved caspase-3,and the activation of checkpoint kinase 1(CHK1)after cisplatin(2.5 and 1.0 μmol/L)treatment.Immunofluorescence was conducted to observe the effect of BCCIP on γ-H2AX expression in GC cells treated with cisplatin(2.5 and 1.0 μmol/L).RESULTS:The BCCIP expression was significantly up-regulated in GC tissues compared with normal tissues(P<0.01).Cisplatin induced up-regulation of BCCIP expression in a dose-and time-depen-dent manner.Knockdown of BCCIP significantly enhanced cisplatin-induced apoptosis(P<0.01)and reduced colony-forming ability(P<0.05)of GC cells.Knockdown of BCCIP promoted the expression of γ-H2AX,but inhibited the activa-tion of CHK1 after cisplatin treatment,with increased protein levels of cleaved caspase-9 and cleaved caspase-3(P<0.01).CONCLUSION:Cisplatin promotes the expression of BCCIP in GC cells.BCCIP confers cisplatin resistance in GC cells by suppressing apoptosis through modulation of DNA damage response pathways.关键词
BRCA2和CDKN1A相互作用蛋白/胃癌/顺铂/化疗耐药/DNA损伤反应/细胞凋亡Key words
BRCA2 and CDKN1A interacting protein/gastric cancer/cisplatin/chemoresistance/DNA damage response/apoptosis分类
临床医学引用本文复制引用
贾哲,翁诺卿,罗辉兴,曾广言,邹鹏,付宗立,周楚洲,饶雄辉,周宇航,江超,靳兴汉..BCCIP通过调节DNA损伤修复途径增强胃癌对顺铂的耐药性[J].中国病理生理杂志,2025,41(5):871-881,11.基金项目
福田区卫生健康公益科研项目(No.FTWS2023073) （No.FTWS2023073）
广东省基础与应用基础研究基金(No.2022A1515111166) （No.2022A1515111166）
深圳市科技计划项目(No.JCYJ20220530144415034) （No.JCYJ20220530144415034）
2024年深圳市宝安区公立医院高质量发展研究项目(No.BAGZL2024009) （No.BAGZL2024009）
