c-Jun诱导HHLA2上调促进EGFR突变型肺腺癌细胞增殖、迁移和侵袭  

Up-regulation of HHLA2 induced by c-Jun promotes the proliferation,migration and invasion of EGFR mutant lung adenocarcinoma

作　　者：刘昕[1,2] 李燕 毛志远[2] 王丽虹 于海燕 孙丽 刘菊琴 孙璐璐 樊再雯 LIU Xin;LI Yan;MAO Zhiyuan;WANG Lihong;YU Haiyan;SUN Li;LIU Juqin;SUN Lulu;FAN Zaiwen(Graduate School of Hebei North University,Hebei Zhangjiakou 075000,China;Department of Oncology,Air Force Medical Center,Beijing 100142,China)

机构地区：[1]河北北方学院研究生院,河北张家口075000 [2]空军特色医学中心肿瘤科,北京100142

出　　处：《现代肿瘤医学》2025年第6期924-931,共8页Journal of Modern Oncology

摘　　要：目的:研究转录因子c-Jun诱导人内源性逆转录病毒H长末端重复关联蛋白2(human endogenous retrovirus-H long terminal repeat-associating protein 2,HHLA2)上调对表皮生长因子受体(epidermal growth factor receptor,EGFR)突变型肺腺癌发生发展的影响。方法:生信分析HHLA2在EGFR突变型和野生型肺腺癌中的表达差异及临床特征以及可能参与的信号通路,预测调控HHLA2的转录因子。将EGFR野生型肺腺癌细胞株A549细胞及EGFR突变型肺腺癌细胞株H1975瞬转质粒c-Jun构建过表达细胞系A549-c-Jun及H1975-c-Jun。并将其分为4组:a组(A549-c-Jun),b组(A549+NC),c组(H1975-c-Jun),d组(H1975+NC),双荧光素酶报告实验验证转录因子c-Jun和HHLA2互作;CCK-8、Transwell、细胞划痕实验分别检测c-Jun过表达前后各组细胞增殖、迁移、侵袭情况;qRT-PCR检测HHLA2 mRNA表达情况;Western blot检测HHLA2蛋白表达量的变化。结果:生信分析表明HHLA2在EGFR突变型的LUAD组织中表达明显高于EGFR野生型(P<0.05);HHLA2高表达组LUAD患者总生存期明显缩短(P<0.05);T分期及HHLA2表达与患者的预后相关。双荧光素酶报告实验显示过表达c-Jun的细胞系荧光强度显著增加(P<0.05);过表达c-Jun转染EGFR突变型肺腺癌细胞后,癌细胞迁移、增殖、侵袭明显增强(P<0.05)。HHLA2在EGFR突变型肺腺癌细胞系中的表达水平升高(P<0.05)。结论:c-Jun诱导HHLA2上调促进EGFR突变型肺腺癌细胞增殖、迁移、侵袭等生物学行为,促进肺腺癌的发生发展。Objective:To investigate the effect of c-Jun-induced up-regulation of HHLA2 on the occurrence and development of EGFR-mutant lung adenocarcinoma.Methods:The differential expression and clinical features of HHLA2 between EGFR mutant and wild type were analyzed,and the possible signaling pathways were involved.The transcription factors regulating HHLA2 were predicted.EGFR wild type lung adenocarcinoma cell line A549 and EGFR mutant lung adenocarcinoma cell line H1975 were used to construct transient plasmid c-Jun overexpression cell lines A549-c-Jun and H1975-c-Jun.The cells were divided into 4 groups:Group a(A549-c-Jun),group b(A549+empty vector),group c(H1975-c-Jun),group d(H1975+empty vector).Dual luciferase reporter assay was used to verify the interaction between transcription factor c-Jun and HHLA2.Cell counting kit-8(CCK-8),Transwell and cell scratch assay were used to detect the proliferation,migration and invasion of each group before and after c-Jun overexpression.qRT-PCR was used to detect the expression of HHLA2 mRNA.The expression of HHLA2 protein was detected by Western blot.Results:The expression of HHLA2 in LUAD tissues with EGFR mutation was significantly higher than that with EGFR wild type(P<0.05).The overall survival of LUAD patients with high HHLA2 expression was significantly shortened(P<0.05).T stage and HHLA2 expression were related to the prognosis of patients.Dual luciferase reporter assay showed that the fluorescence intensity of c-Jun overexpressed cell lines was significantly increased(P<0.05).Overexpression of c-Jun significantly enhanced the migration,proliferation and invasion of EGFR-mutant lung adenocarcinoma cells(P<0.05).The expression level of HHLA2 was increased in EGFR-mutant lung adenocarcinoma cell lines(P<0.05).Conclusion:c-Jun-induced up-regulation of HHLA2 promotes the proliferation,migration,invasion and other biological behaviors of EGFR-mutant lung adenocarcinoma cells,and promotes the occurrence and development of lung adenocarcinoma.

关 键 词：HHLA2 C-JUN 肺腺癌 EGFR突变 

分 类 号：R734.2[医药卫生—肿瘤]