• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

多重筛选鉴定出 RAS 旁系同源物 HRAS 和 NRAS 是 KRAS 驱动的肺癌生长的抑制剂。

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.

机构信息

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Department of Biology, Stanford University, Stanford, CA, USA.

出版信息

Nat Cell Biol. 2023 Jan;25(1):159-169. doi: 10.1038/s41556-022-01049-w. Epub 2023 Jan 12.

DOI:10.1038/s41556-022-01049-w
PMID:36635501
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10521195/
Abstract

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.

摘要

致癌 KRAS 突变大约发生在 30%的肺腺癌中。尽管经过几十年的努力，致癌 KRAS 驱动的肺癌仍然难以治疗，并且我们对 RAS 信号转导的调节因子的了解并不完整。在这里，我们结合遗传工程小鼠模型中的多重体细胞 CRISPR/Cas9 基因组编辑、肿瘤条形码和高通量条形码测序，揭示了不同 KRAS 相互作用蛋白对肺癌生长的影响。通过一系列在同源肺癌模型中的 CRISPR/Cas9 筛选，我们表明 HRAS 和 NRAS 是体内 KRAS 驱动肿瘤生长的抑制剂，并在致癌 KRAS 驱动的人类肺癌细胞系中证实了这些作用。从机制上讲，RAS 同源物与致癌 KRAS 相互作用，抑制 KRAS-KRAS 相互作用，并降低下游 ERK 信号。此外，在致癌 KRAS 驱动的人类肿瘤中鉴定的 HRAS 和 NRAS 突变部分消除了这种效应。通过比较 HRAS 和 NRAS 在致癌 KRAS 和致癌 BRAF 驱动的肺癌模型中的肿瘤抑制作用，我们证实 RAS 同源物是体内 KRAS 驱动肺癌的特异性抑制剂。我们的研究概述了一种技术途径，可在体内以多重方式揭示致癌 KRAS 驱动的癌症的正调节剂和负调节剂，并强调了 RAS 同源物失衡在致癌 KRAS 驱动的肺癌中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/6b47ee1148eb/nihms-1896783-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/2be4409c3cac/nihms-1896783-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/d39f671eb362/nihms-1896783-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/5b23dab92b97/nihms-1896783-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/5bdaf105cc5e/nihms-1896783-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/209fc148bd30/nihms-1896783-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/2d9a7296df6b/nihms-1896783-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/046b40b0beeb/nihms-1896783-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/bff722f2b2d0/nihms-1896783-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/02f3129f37a8/nihms-1896783-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/63d384daa868/nihms-1896783-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/f79d5f8aea9e/nihms-1896783-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/e002e1a5fd3e/nihms-1896783-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/29ec74d27de7/nihms-1896783-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/43f8c33e7ca7/nihms-1896783-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/db14aefce632/nihms-1896783-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/6b47ee1148eb/nihms-1896783-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/2be4409c3cac/nihms-1896783-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/d39f671eb362/nihms-1896783-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/5b23dab92b97/nihms-1896783-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/5bdaf105cc5e/nihms-1896783-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/209fc148bd30/nihms-1896783-f0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/2d9a7296df6b/nihms-1896783-f0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/046b40b0beeb/nihms-1896783-f0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/bff722f2b2d0/nihms-1896783-f0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/02f3129f37a8/nihms-1896783-f0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/63d384daa868/nihms-1896783-f0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/f79d5f8aea9e/nihms-1896783-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/e002e1a5fd3e/nihms-1896783-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/29ec74d27de7/nihms-1896783-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/43f8c33e7ca7/nihms-1896783-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/db14aefce632/nihms-1896783-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28d9/10521195/6b47ee1148eb/nihms-1896783-f0006.jpg

相似文献

1
Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.多重筛选鉴定出 RAS 旁系同源物 HRAS 和 NRAS 是 KRAS 驱动的肺癌生长的抑制剂。
Nat Cell Biol. 2023 Jan;25(1):159-169. doi: 10.1038/s41556-022-01049-w. Epub 2023 Jan 12.
2
Reduced HRAS G12V-Driven Tumorigenesis of Cell Lines Expressing KRAS C118S.表达KRAS C118S的细胞系中HRAS G12V驱动的肿瘤发生减少。
PLoS One. 2015 Apr 22;10(4):e0123918. doi: 10.1371/journal.pone.0123918. eCollection 2015.
3
A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation.野生型 Ras 同工型在突变 KRas 驱动的信号转导和转化中的需求。
Biochem J. 2013 Jun 1;452(2):313-20. doi: 10.1042/BJ20121578.
4
Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants.非经典和新型结直肠癌 KRAS 和 NRAS 突变体的非冗余和重叠致癌读出。
Cells. 2019 Dec 3;8(12):1557. doi: 10.3390/cells8121557.
5
Calmodulin and IQGAP1 activation of PI3Kα and Akt in KRAS, HRAS and NRAS-driven cancers.钙调蛋白和 IQGAP1 激活 KRAS、HRAS 和 NRAS 驱动的癌症中的 PI3Kα 和 Akt。
Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt B):2304-2314. doi: 10.1016/j.bbadis.2017.10.032. Epub 2017 Oct 31.
6
RAS/RAF mutations and their associations with epigenetic alterations for distinct pathways in Vietnamese colorectal cancer.越南结直肠癌中不同通路的 RAS/RAF 突变及其与表观遗传改变的关联。
Pathol Res Pract. 2020 Apr;216(4):152898. doi: 10.1016/j.prp.2020.152898. Epub 2020 Feb 17.
7
Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation.致癌性 RAS 异构体显示出对鸟嘌呤核苷酸交换因子 SOS2 的分级需求，以介导细胞转化。
Sci Signal. 2018 Sep 4;11(546):eaar8371. doi: 10.1126/scisignal.aar8371.
8
Comparison of liver oncogenic potential among human RAS isoforms.人类RAS亚型之间肝脏致癌潜力的比较。
Oncotarget. 2016 Feb 9;7(6):7354-66. doi: 10.18632/oncotarget.6931.
9
Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis.野生型和突变型 Ras 基因在肺和皮肤肿瘤发生中的相互作用。
Oncogene. 2013 Aug 22;32(34):4028-33. doi: 10.1038/onc.2012.404. Epub 2012 Sep 3.
10
Extended-spectrum of and mutations in lung cancer tissue specimens obtained with bronchoscopy.支气管镜获取的肺癌组织标本中 和 基因突变的广谱性。
Indian J Cancer. 2022 Apr-Jun;59(2):236-243. doi: 10.4103/ijc.IJC_766_19.

引用本文的文献

1
Proto-Oncogene HRAS Transcript Level and Overall Survival in Stages II and III Colorectal Cancer.原癌基因HRAS转录水平与II期和III期结直肠癌的总生存期
Cancer Med. 2025 Aug;14(15):e71114. doi: 10.1002/cam4.71114.
2
Methods and applications of in vivo CRISPR screening.体内CRISPR筛选的方法与应用
Nat Rev Genet. 2025 Jul 29. doi: 10.1038/s41576-025-00873-8.
3
Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis.早期肺癌中的表观遗传修饰：发病机制、生物标志物与早期诊断
MedComm (2020). 2025 Feb 21;6(3):e70080. doi: 10.1002/mco2.70080. eCollection 2025 Mar.
4
Experimental variables determine the outcome of RAS-RAS interactions.实验变量决定了RAS-RAS相互作用的结果。
J Biol Chem. 2024 Nov;300(11):107859. doi: 10.1016/j.jbc.2024.107859. Epub 2024 Oct 5.
5
A new model for the inference of biological entities states: Ternary Entity State Inference System.一种用于推断生物实体状态的新模型：三元实体状态推断系统。
Heliyon. 2024 Sep 6;10(18):e37578. doi: 10.1016/j.heliyon.2024.e37578. eCollection 2024 Sep 30.
6
Structural modifications and kinetic effects of interactions with and : an comparative analysis of mutants.与……相互作用的结构修饰和动力学效应以及……：突变体的比较分析。 （由于原文中部分关键内容缺失，可能翻译得不够准确完整，你可以补充完整原文以便更精准翻译。）
Front Mol Biosci. 2024 Aug 9;11:1436976. doi: 10.3389/fmolb.2024.1436976. eCollection 2024.
7
Capturing RAS oligomerization on a membrane.在膜上捕获 RAS 寡聚体。
Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2405986121. doi: 10.1073/pnas.2405986121. Epub 2024 Aug 15.
8
Functional and structural insights into RAS effector proteins.RAS 效应蛋白的功能和结构见解。
Mol Cell. 2024 Aug 8;84(15):2807-2821. doi: 10.1016/j.molcel.2024.06.027. Epub 2024 Jul 17.
9
Applications and advancements of CRISPR-Cas in the treatment of lung cancer.CRISPR-Cas在肺癌治疗中的应用与进展
Front Cell Dev Biol. 2023 Dec 11;11:1295084. doi: 10.3389/fcell.2023.1295084. eCollection 2023.
10
Applications of CRISPR screening to lung cancer treatment.CRISPR筛选在肺癌治疗中的应用。
Front Cell Dev Biol. 2023 Dec 15;11:1295555. doi: 10.3389/fcell.2023.1295555. eCollection 2023.