Knockdown of IGF2BP2 overcomes cisplatin-resistance in lung cancer through downregulating Spon2 gene.

IF 2.7 3区 生物学
Shilei Zhang, Ting Dou, Hong Li, Hongfang Yu, Wei Zhang, Liping Sun, Jingwen Yang, Zhenfei Wang, Hao Yang
{"title":"Knockdown of IGF2BP2 overcomes cisplatin-resistance in lung cancer through downregulating Spon2 gene.","authors":"Shilei Zhang, Ting Dou, Hong Li, Hongfang Yu, Wei Zhang, Liping Sun, Jingwen Yang, Zhenfei Wang, Hao Yang","doi":"10.1186/s41065-024-00360-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cisplatin (DDP) resistance has long posed a challenge in the clinical treatment of lung cancer (LC). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) has been identified as an oncogenic factor in LC, whereas its specific role in DDP resistance in LC remains unclear.</p><p><strong>Results: </strong>In this study, we investigated the role of IGF2BP2 on DDP resistance in DDP-resistant A549 cells (A549/DDP) in vitro and in a DDP-resistant lung tumor-bearing mouse model in vivo. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted to identify the potential mRNAs regulated by IGF2BP2, an N6-methyladenosine (m6A) regulator, in the tumor tissues of mice. Compared to normal tissues, IGF2BP2 levels were increased in LC tissues and in relapsed/resistant LC tissues. Most importantly, IGF2BP2 levels were significantly higher in relapsed/resistant LC tissues than in LC tissues. Significantly, knockdown of IGF2BP2 or DDP treatment inhibited A549 cell viability, migration, and cell cycle progression. Consistently, DDP treatment suppressed the viability and migration and triggered cell cycle arrest in A549/DDP cells in vitro, as well as reduced tumor volume and weight of A549/DDP tumor-bearing mice; meanwhile, the combination of DDP and IGF2BP2 siRNA further significantly inhibited A549/DDP cell growth in vitro and in vivo compared to DDP treatment alone. Furthermore, MeRIP-seq data showed that IGF2BP2 downregulation remarkably elevated m6A levels of spondin 2 (Spon2) and reduced mRNA levels of Spon2 in tumor tissues from A549 tumor-bearing mice. Meanwhile, the combination of DDP and IGF2BP2 siRNA notably reduced Spon2 levels, as well as inhibited the viability and induced apoptosis in A549/DDP cells; however, these effects were reversed by Spon2 overexpression.</p><p><strong>Conclusion: </strong>Collectively, downregulation of IGF2BP2 could overcome DDP resistance in LC through declining the Spon2 gene expression in an m6A-dependent manner. These results may provide a new strategy for overcoming DDP resistance in LC.</p>","PeriodicalId":12862,"journal":{"name":"Hereditas","volume":"161 1","pages":"55"},"PeriodicalIF":2.7000,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681704/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hereditas","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s41065-024-00360-w","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Cisplatin (DDP) resistance has long posed a challenge in the clinical treatment of lung cancer (LC). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) has been identified as an oncogenic factor in LC, whereas its specific role in DDP resistance in LC remains unclear.

Results: In this study, we investigated the role of IGF2BP2 on DDP resistance in DDP-resistant A549 cells (A549/DDP) in vitro and in a DDP-resistant lung tumor-bearing mouse model in vivo. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted to identify the potential mRNAs regulated by IGF2BP2, an N6-methyladenosine (m6A) regulator, in the tumor tissues of mice. Compared to normal tissues, IGF2BP2 levels were increased in LC tissues and in relapsed/resistant LC tissues. Most importantly, IGF2BP2 levels were significantly higher in relapsed/resistant LC tissues than in LC tissues. Significantly, knockdown of IGF2BP2 or DDP treatment inhibited A549 cell viability, migration, and cell cycle progression. Consistently, DDP treatment suppressed the viability and migration and triggered cell cycle arrest in A549/DDP cells in vitro, as well as reduced tumor volume and weight of A549/DDP tumor-bearing mice; meanwhile, the combination of DDP and IGF2BP2 siRNA further significantly inhibited A549/DDP cell growth in vitro and in vivo compared to DDP treatment alone. Furthermore, MeRIP-seq data showed that IGF2BP2 downregulation remarkably elevated m6A levels of spondin 2 (Spon2) and reduced mRNA levels of Spon2 in tumor tissues from A549 tumor-bearing mice. Meanwhile, the combination of DDP and IGF2BP2 siRNA notably reduced Spon2 levels, as well as inhibited the viability and induced apoptosis in A549/DDP cells; however, these effects were reversed by Spon2 overexpression.

Conclusion: Collectively, downregulation of IGF2BP2 could overcome DDP resistance in LC through declining the Spon2 gene expression in an m6A-dependent manner. These results may provide a new strategy for overcoming DDP resistance in LC.

IGF2BP2下调通过下调Spon2基因克服肺癌顺铂耐药。
背景:顺铂耐药一直是肺癌(LC)临床治疗的难题。胰岛素样生长因子2结合蛋白2 (IGF2BP2)已被确定为LC中的一个致癌因子,但其在LC中DDP耐药中的具体作用尚不清楚。结果:本研究在体外和体内肺荷瘤小鼠DDP耐药模型中,研究了IGF2BP2对DDP耐药A549细胞(A549/DDP) DDP耐药性的影响。此外,采用甲基化RNA免疫沉淀测序(MeRIP-seq)方法鉴定小鼠肿瘤组织中受n6 -甲基腺苷(m6A)调节剂IGF2BP2调控的潜在mrna。与正常组织相比,LC组织和复发/耐药LC组织中IGF2BP2水平升高。最重要的是,复发/耐药LC组织中的IGF2BP2水平明显高于LC组织。值得注意的是,IGF2BP2或DDP的敲除抑制了A549细胞的活力、迁移和细胞周期进展。在体外实验中,DDP抑制A549/DDP细胞的活力和迁移,引发细胞周期阻滞,并减少A549/DDP荷瘤小鼠的肿瘤体积和重量;同时,与DDP单独治疗相比,DDP联合IGF2BP2 siRNA在体外和体内进一步显著抑制了A549/DDP细胞的生长。此外,MeRIP-seq数据显示,IGF2BP2下调显著提高了A549荷瘤小鼠肿瘤组织中spondin 2 (Spon2)的m6A水平,并降低了Spon2的mRNA水平。同时,DDP与IGF2BP2 siRNA联用可显著降低A549/DDP细胞的Spon2水平,抑制细胞活力,诱导细胞凋亡;然而,这些影响被Spon2过表达逆转。结论:综上所述,IGF2BP2下调可通过m6a依赖性降低Spon2基因的表达来克服LC对DDP的抗性。这些结果可能为克服LC对DDP的抗性提供新的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Hereditas
Hereditas Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.80
自引率
3.70%
发文量
0
期刊介绍: For almost a century, Hereditas has published original cutting-edge research and reviews. As the Official journal of the Mendelian Society of Lund, the journal welcomes research from across all areas of genetics and genomics. Topics of interest include human and medical genetics, animal and plant genetics, microbial genetics, agriculture and bioinformatics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信