低氧诱导的肺腺癌中miR-210-3p的表达通过调节CCL2介导的单核细胞浸润来增强肿瘤的发展。

IF 5 2区 医学 Q1 ONCOLOGY
Molecular Oncology Pub Date : 2024-05-01 Epub Date: 2024-03-22 DOI:10.1002/1878-0261.13260
Leena Arora, Debarun Patra, Soumyajit Roy, Sidhanta Nanda, Navneet Singh, Anita K Verma, Anuradha Chakraborti, Suman Dasgupta, Durba Pal
{"title":"低氧诱导的肺腺癌中miR-210-3p的表达通过调节CCL2介导的单核细胞浸润来增强肿瘤的发展。","authors":"Leena Arora, Debarun Patra, Soumyajit Roy, Sidhanta Nanda, Navneet Singh, Anita K Verma, Anuradha Chakraborti, Suman Dasgupta, Durba Pal","doi":"10.1002/1878-0261.13260","DOIUrl":null,"url":null,"abstract":"<p><p>In most cancers, tumor hypoxia downregulates the expression of C-C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung-adenocarcinoma human samples for hypoxia-inducible factor 1-alpha (HIF-1A), microRNA-210-3p (mir-210-3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia-induced miR-210-3p in the regulation of CCL2 expression and macrophage polarization. HIF-1Α stabilization increases miR-210-3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR-210-3p directly binds to the 3'untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR-210-3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR-210-3p mimic-transfected HIF-1A silenced cancer cells. In contrast, inhibition of miR-210-3p in HIF-1A-overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti-hsa-miR-210-3p-locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR-210-3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.</p>","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11077004/pdf/","citationCount":"0","resultStr":"{\"title\":\"Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2 mediated monocyte infiltration.\",\"authors\":\"Leena Arora, Debarun Patra, Soumyajit Roy, Sidhanta Nanda, Navneet Singh, Anita K Verma, Anuradha Chakraborti, Suman Dasgupta, Durba Pal\",\"doi\":\"10.1002/1878-0261.13260\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>In most cancers, tumor hypoxia downregulates the expression of C-C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung-adenocarcinoma human samples for hypoxia-inducible factor 1-alpha (HIF-1A), microRNA-210-3p (mir-210-3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia-induced miR-210-3p in the regulation of CCL2 expression and macrophage polarization. HIF-1Α stabilization increases miR-210-3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR-210-3p directly binds to the 3'untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR-210-3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR-210-3p mimic-transfected HIF-1A silenced cancer cells. In contrast, inhibition of miR-210-3p in HIF-1A-overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti-hsa-miR-210-3p-locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR-210-3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.</p>\",\"PeriodicalId\":51134,\"journal\":{\"name\":\"Molecular Oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2024-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11077004/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/1878-0261.13260\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/22 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/1878-0261.13260","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

在大多数癌症中,肿瘤缺氧下调C-C基序趋化因子2(CCL2)的表达,这种下调与单核细胞浸润和肿瘤进展有关;然而,其分子机制尚不清楚。我们比较了非癌性和肺腺癌人类样本的缺氧诱导因子1-α(HIF-1A)、微小RNA-210-3p(mir-210-3p)和CCL2水平。对肺腺癌细胞系和3D肿瘤球体进行了机制研究,以了解缺氧诱导的miR-210-3p在CCL2表达和巨噬细胞极化调节中的作用。HIF-1 A稳定可增加肺腺癌中miR-210-3p的水平,并通过抑制CCL2的表达来损害单核细胞的浸润。从机制上讲,miR-210-3p直接与CCL2 mRNA的3’非翻译区(UTR)结合并使其沉默。抑制miR-210-3p可显著下调缺氧对CCL2表达的影响。在miR-210-3p模拟转染的HIF-1A沉默的癌症细胞中,单核细胞迁移受到显著阻碍。相反,在HIF-1A过表达的细胞中抑制miR-210-3p显著恢复了单核细胞的迁移,突出了miR-210-3p水平与肿瘤单核细胞负荷之间的直接联系。此外,miR-210-3p在3D肿瘤球体中的抑制促进单核细胞募集并向抗肿瘤M1表型倾斜。在肺肿瘤异种移植物斑马鱼模型中递送抗-hsa-miR-210-3p锁定核酸(LNA)导致肿瘤消退,这表明miR-210-3p可能是针对肺腺癌的免疫调节治疗策略的一个有前途的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2 mediated monocyte infiltration.

In most cancers, tumor hypoxia downregulates the expression of C-C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung-adenocarcinoma human samples for hypoxia-inducible factor 1-alpha (HIF-1A), microRNA-210-3p (mir-210-3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia-induced miR-210-3p in the regulation of CCL2 expression and macrophage polarization. HIF-1Α stabilization increases miR-210-3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR-210-3p directly binds to the 3'untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR-210-3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR-210-3p mimic-transfected HIF-1A silenced cancer cells. In contrast, inhibition of miR-210-3p in HIF-1A-overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti-hsa-miR-210-3p-locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR-210-3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Oncology
Molecular Oncology 医学-肿瘤学
CiteScore
12.60
自引率
1.50%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.
×
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