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在Wnt驱动的长链非编码转录组中识别结直肠癌特异性的脆弱点。

Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome.

作者信息

Schwarzmueller Laura J, Adam Ronja S, Moreno Leandro F, Nijman Lisanne E, Logiantara Adrian, Eleonora Steven, Bril Oscar, Vromans Sophie, de Groot Nina E, Giugliano Francesca Paola, Stepanova Ekaterina, Muncan Vanesa, Elbers Clara C, Lenos Kristiaan J, Zwijnenburg Danny A, van Eijndhoven Monique A J, Pegtel Dirk Michiel, van Neerven Sanne M, Loayza-Puch Fabricio, Dadali Tulin, Broom Wendy J, Maier Martin A, Koster Jan, Vermeulen Louis, Léveillé Nicolas

机构信息

Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Oncode Institute, Amsterdam, The Netherlands.

出版信息

Gut. 2025 Mar 6;74(4):571-585. doi: 10.1136/gutjnl-2024-332752.

DOI:10.1136/gutjnl-2024-332752
PMID:39562049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12013597/
Abstract

BACKGROUND

Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved.

OBJECTIVE

In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets.

DESIGN

We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC.

RESULTS

We uncovered that is essential for cancer cell clonogenic outgrowth. Mechanistically, regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target RNA .

CONCLUSION

We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.

摘要

背景

Wnt信号通路异常激活是结直肠癌（CRC）的关键驱动因素，对维持肿瘤生长和进展至关重要。尽管Wnt信号级联的下游蛋白质编码靶基因已为人熟知，但长链非编码转录组尚未完全解析。

目的

在本研究中，我们旨在全面揭示Wnt调控的长链非编码转录组，并开发关键分子作为新型治疗靶点。

设计

我们使用全局转录测序来定义CRC中β-连环蛋白调控的长链非编码RNA（lncRNAs）。随后使用CRISPRi敲除筛选来确定这些lncRNAs的一个子集对CRC长期扩增的功能相关性。

结果

我们发现 对癌细胞克隆生长至关重要。从机制上讲， 调节MYC表达水平以促进CRC干细胞功能并防止终末分化。此外，我们开发了有效的基于小干扰RNA（siRNA）的疗法来靶向 RNA。

结论

我们提出癌症特异性Wnt调控的lncRNAs为干扰Wnt信号通路提供了新的治疗机会，而Wnt信号通路迄今为止一直难以实现有效的药物抑制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/7754df82e317/gutjnl-74-4-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/af19391a2364/gutjnl-74-4-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/11d8ab1ca9e2/gutjnl-74-4-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/1029fdabc67d/gutjnl-74-4-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/f8b3c8c5b946/gutjnl-74-4-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/a843a3e69ab7/gutjnl-74-4-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/b7407f1a5230/gutjnl-74-4-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/7754df82e317/gutjnl-74-4-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/af19391a2364/gutjnl-74-4-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/11d8ab1ca9e2/gutjnl-74-4-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/1029fdabc67d/gutjnl-74-4-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/f8b3c8c5b946/gutjnl-74-4-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/a843a3e69ab7/gutjnl-74-4-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a395/12013597/b7407f1a5230/gutjnl-74-4-g006.jpg
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本文引用的文献

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Cells. 2023 Apr 8;12(8):1110. doi: 10.3390/cells12081110.
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Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer.Notch相关长链非编码RNA对结直肠癌表观遗传修饰的调控机制
Cancer Cell Int. 2022 Oct 13;22(1):316. doi: 10.1186/s12935-022-02736-2.
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MYC: a complex problem.MYC：一个复杂的问题。
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The MYC oncogene - the grand orchestrator of cancer growth and immune evasion.MYC 癌基因——癌症生长和免疫逃逸的总指挥。
Nat Rev Clin Oncol. 2022 Jan;19(1):23-36. doi: 10.1038/s41571-021-00549-2. Epub 2021 Sep 10.
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Noncoding RNA therapeutics - challenges and potential solutions.非编码 RNA 治疗学——挑战与潜在解决方案。
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Emerging Role and Therapeutic Potential of lncRNAs in Colorectal Cancer.长链非编码RNA在结直肠癌中的新兴作用及治疗潜力
Cancers (Basel). 2020 Dec 19;12(12):3843. doi: 10.3390/cancers12123843.
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The long noncoding RNA LUCAT1 promotes colorectal cancer cell proliferation by antagonizing Nucleolin to regulate MYC expression.长链非编码 RNA LUCAT1 通过拮抗核仁蛋白来调节 MYC 表达促进结直肠癌细胞增殖。
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