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组织再生和癌症中MYC上游超级增强子区域的共同需求。

Shared requirement for MYC upstream super-enhancer region in tissue regeneration and cancer.

作者信息

Sur Inderpreet, Zhao Wenshuo, Zhang Jilin, Kling Pilström Margareta, Webb Anna T, Cheng Huaitao, Ristimäki Ari, Katajisto Pekka, Enge Martin, Rannikmae Helena, de la Roche Marc, Taipale Jussi

机构信息

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

出版信息

Life Sci Alliance. 2025 Apr 3;8(6). doi: 10.26508/lsa.202403090. Print 2025 Jun.

DOI:10.26508/lsa.202403090
PMID:40180576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11969384/
Abstract

Cancer has been characterized as a wound that does not heal. Malignant cells are morphologically distinct from normal proliferating cells but have extensive similarities to tissues undergoing wound healing and/or regeneration. The mechanistic basis of this similarity has, however, remained enigmatic. Here, we show that the genomic region upstream of , which carries more cancer susceptibility in humans than any other genomic region, is required for intestinal regeneration after radiation damage. Failure to regenerate is associated with inefficient /Sca1 stem/progenitor cell mobilization, and almost complete failure to re-establish Lgr5+ cell compartment in the intestinal crypts. The upstream region is also critical for growth of adult intestinal cells in 3D organoid culture. We show that culture conditions recapitulating most aspects of adult normal tissue architecture still reprogram normal cells to proliferate using a mechanism similar to that employed by cancer cells. Our results establish a function for the super-enhancer region as the genetic link between tissue regeneration and tumorigenesis, and demonstrates that normal tissue renewal and regeneration of tissues after severe damage are mechanistically distinct.

摘要

癌症被描述为一种无法愈合的伤口。恶性细胞在形态上与正常增殖细胞不同，但与正在经历伤口愈合和/或再生的组织有广泛的相似性。然而，这种相似性的机制基础仍然是个谜。在这里，我们表明，在人类中携带比任何其他基因组区域更多癌症易感性的[具体基因名称缺失]上游基因组区域，是辐射损伤后肠道再生所必需的。无法再生与/Sca1干细胞/祖细胞动员效率低下有关，并且几乎完全无法在肠隐窝中重新建立Lgr5 +细胞区室。[具体基因名称缺失]上游区域对于三维类器官培养中成年肠道细胞的生长也至关重要。我们表明，模拟成年正常组织结构大多数方面的培养条件仍然会使正常细胞通过类似于癌细胞所采用的机制重新编程以进行增殖。我们的结果确立了[具体基因名称缺失]超级增强子区域作为组织再生与肿瘤发生之间的遗传联系的功能，并证明正常组织更新和严重损伤后组织的再生在机制上是不同的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/f989cc441373/LSA-2024-03090_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/ef4275a2b101/LSA-2024-03090_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/42b9378203da/LSA-2024-03090_FigS1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/c58d138d378c/LSA-2024-03090_FigS2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/e15099bc7db8/LSA-2024-03090_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/49fe636b1a71/LSA-2024-03090_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/dd4a87d9f285/LSA-2024-03090_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/09a9d51dc7cd/LSA-2024-03090_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/f664b93930c5/LSA-2024-03090_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/12bcb23e7e25/LSA-2024-03090_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/d72fdbf9c822/LSA-2024-03090_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/8b72e427397d/LSA-2024-03090_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/f989cc441373/LSA-2024-03090_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/ef4275a2b101/LSA-2024-03090_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/42b9378203da/LSA-2024-03090_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/52571c7ec677/LSA-2024-03090_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/c58d138d378c/LSA-2024-03090_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/2673abf1d351/LSA-2024-03090_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/e15099bc7db8/LSA-2024-03090_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/49fe636b1a71/LSA-2024-03090_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/dd4a87d9f285/LSA-2024-03090_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/09a9d51dc7cd/LSA-2024-03090_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/f664b93930c5/LSA-2024-03090_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/12bcb23e7e25/LSA-2024-03090_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/d72fdbf9c822/LSA-2024-03090_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/8b72e427397d/LSA-2024-03090_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08eb/11969384/f989cc441373/LSA-2024-03090_Fig7.jpg

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