上海交通大学学报（医学版）

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (11): 1407-1420.doi: 10.3969/j.issn.1674-8115.2025.11.001

• 创新团队成果专栏 •    

长非编码RNA LINC00467在肺腺癌中的表达及其影响肺腺癌进展的机制研究

郭琳琰1(), 张海龙2, 郑超1(), 雷鸣1()   

  1. 1.上海交通大学医学院附属第九人民医院上海精准医学研究院，上海 200125
    2.中山大学医学院分子肿瘤中心，深圳 518107
  • 收稿日期:2025-06-26 接受日期:2025-08-18 出版日期:2025-11-28 发布日期:2025-12-03
  • 通讯作者: 雷　鸣，研究员，博士；电子信箱：leim@shsmu.edu.cn
    郑　超，助理研究员，博士；电子信箱：zhengchao@shsmu.edu.cn。
  • 作者简介:雷鸣(研究员/博士)　张燕捷(主任医师/博士)　曹禹(研究员/博士)
    雷鸣（1971一），2001年博士毕业于美国哈佛大学。2001至2004年在美国科罗拉多大学波尔德分校从事博士后研究。2004至2011年在美国密西根大学医学院生物化学系工作，历任助理教授、副教授。2011年6月至2017年8月，担任国家蛋白质科学中心（上海）主任，中科院生化细胞所副所长。2017年9月至今，担任上海交通大学医学院附属第九人民医院上海精准医学研究院执行院长。现任亚太蛋白质协会执行委员、中国生物物理学会副理事长。目前担任Biological Chemistry杂志副主编、Science Bulletin杂志执行编委。
    LEI Ming (1971-), received a doctor degree of biophysics from Harvard University in 2001. During 2001 and 2004, he received the postdoctoral training at University of Colorado at Boulder. From 2004, he began the academic career at the University of Michigan as an assistant professor and became tenured associate professor at 2010. From 2011 to 2017, he was deputy director of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences and director of National Center for Protein Science Shanghai, China. From 2017 to present, he has been executive director of Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. He is an executive committee member of Asia Pacific Protein Association and deputy secretary of Biophysical Society of China. He is also an associate editor of Biological Chemistry and executive editor of Science Bulletin.主要研究方向
  • 基金资助:
    国家自然科学基金(82403599)

Expression of long noncoding RNA LINC00467 and its mechanism in affecting lung adenocarcinoma progression

GUO Linyan1(), ZHANG Hailong2, ZHENG Chao1(), LEI Ming1()   

  1. 1.Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China
    2.Molecular Cancer Center, Sun Yat-sen University School of Medicine, Shenzhen 518107, China
  • Received:2025-06-26 Accepted:2025-08-18 Online:2025-11-28 Published:2025-12-03
  • Contact: LEI Ming, E-mail: leim@shsmu.edu.cn
    ZHENG Chao, E-mail: zhengchao@shsmu.edu.cn.
  • Supported by:
    National Natural Science Foundation of China(82403599)

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摘要：

目的·探究长非编码RNA（long noncoding RNA，lncRNA）LINC00467在肺腺癌（lung adenocarcinoma，LUAD）中的表达情况及其对患者不良预后的影响，并揭示其调控LUAD发生发展的作用及潜在分子机制。方法·首先，利用癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库中的肿瘤样本数据，分析LINC00467在LUAD组织中的表达水平及其与患者生存期的相关性。其次，构建LINC00467稳定敲低LUAD细胞系，通过细胞表型实验（即活细胞成像检测细胞增殖实验、平板克隆形成实验、细胞划痕实验）及裸鼠皮下成瘤实验，评估LINC00467对LUAD细胞增殖、克隆形成、迁移及成瘤能力的影响。进一步，通过转录组测序（RNA sequencing，RNA-seq）技术、差异表达基因（differentially expressed gene，DEG）分析和hallmark gene sets富集分析，探究LINC00467调控肿瘤细胞的相关信号通路，并利用蛋白质印迹法（Western blotting）验证其对肿瘤细胞通路的影响。最后，通过RNA pull-down联合蛋白质谱以及免疫共沉淀（co-immunoprecipitation，co-IP）实验，筛选并验证LINC00467的相互作用蛋白。结果·TCGA数据库的肿瘤样本数据的分析结果表明LINC00467在LUAD中异常高表达，且其表达水平与LUAD患者的生存期呈负相关（P=0.004）。细胞表型实验及裸鼠皮下成瘤实验的结果均显示，敲低LINC00467可显著抑制LUAD细胞的增殖、克隆形成、迁移和体内成瘤的能力（均P<0.05）。RNA-seq、DEG分析、hallmark gene sets富集分析及蛋白质印迹的结果均表明，敲低LINC00467可抑制核因子κB（nuclear factor kappa-B，NF-κB）信号通路的激活。RNA pull-down联合蛋白质谱和co-IP的结果表明LINC00467与酪蛋白激酶2α2（casein kinase 2 alpha 2，CSNK2A2）存在相互作用，并促进NF-κB p65的磷酸化。结论·LINC00467在LUAD组织中的高表达与患者预后呈负相关；LINC00467可以与CSNK2A2相互作用，促进NF-κB p65的磷酸化，激活NF-κB通路，促进LUAD增殖、克隆形成、迁移和体内成瘤。

关键词: 长非编码RNA, LINC00467, 肺腺癌, 核因子κB, 酪蛋白激酶2α2

Abstract:

Objective ·To investigate the expression of long noncoding RNA (lncRNA) LINC00467 in lung adenocarcinoma (LUAD) and its impact on the poor prognosis of patients, as well as its functional role and underlying molecular mechanisms in the occurrence and development of LUAD. Methods ·First, tumor sample data from The Cancer Genome Atlas (TCGA) database were utilized to analyze the expression levels of LINC00467 in LUAD tissues and its correlation with patient survival. Second, a stable LINC00467-knockdown LUAD cell line was established, and the effects of LINC00467 on LUAD cell proliferation, colony formation, migration, and tumorigenicity were assessed through cell phenotypic experiments (including live-cell imaging for cell proliferation analysis, plate colony formation assays, and wound healing assays) and nude mouse tumor formation experiments. Furthermore, RNA sequencing (RNA-seq), differentially expressed genes (DEGs) analysis, and hallmark gene sets enrichment analysis were performed to identify signaling pathways regulated by LINC00467, and Western blotting was used to validate its impact on tumor cell pathways. Finally, RNA pull-down combined with mass spectrometry and co-immunoprecipitation (co-IP) assays were conducted to filter and identify LINC00467-interacting proteins. Results ·Analysis of tumor sample data from the TCGA database showed that LINC00467 was highly expressed in LUAD, and its expression level was negatively correlated with overall survival in LUAD patients (P=0.004). Cell phenotypic experiments and nude mouse tumor formation experiments demonstrated that LINC00467 knockdown significantly inhibited the proliferation, colony formation, migration and in vivo tumorigenesis of LUAD cells (all P<0.05). RNA-seq, DEGs analysis, hallmark gene sets enrichment analysis, and Western blotting indicated that knockdown of LINC00467 suppressed the activation of nuclear factor kappa-B (NF-κB) signaling pathway. RNA pull-down combined with mass spectrometry and co-IP assays demonstrated that LINC00467 interacted with casein kinase 2 alpha 2 (CSNK2A2) and promoted the phosphorylation of NF-κB p65. Conclusion ·High expression of LINC00467 in LUAD tissues is negatively correlated with patient prognosis. LINC00467 can interact with CSNK2A2, promote the phosphorylation of NF-κB p65, activate the NF-κB pathway, and enhance LUAD proliferation, colony formation, migration, and in vivo tumorigenesis.

Key words: long noncoding RNA (lncRNA), LINC00467, lung adenocarcinoma (LUAD), nuclear factor kappa-B (NF-κB), casein kinase 2 alpha 2 (CSNK2A2)

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