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肠神经元 Ndrg4 的缺失通过增加 Nid1 和 Fbln2 的释放促进结直肠癌的发生。

Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2.

机构信息

Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.

出版信息

EMBO Rep. 2021 Jun 4;22(6):e51913. doi: 10.15252/embr.202051913. Epub 2021 Apr 23.

DOI:10.15252/embr.202051913
PMID:33890711
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8183412/
Abstract

The N-Myc Downstream-Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4 ) CRC models and an indirect co-culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4 ENS cell secretome, which is enriched for Nidogen-1 (Nid1) and Fibulin-2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS-derived Nidogen-1 and Fibulin-2 enhance colorectal carcinogenesis.

摘要

N- 神经纤毛蛋白下调基因 4（NDRG4）是结直肠癌（CRC）的一个重要生物标志物，它在肠神经元中特异性表达。考虑到神经是肿瘤微环境的重要组成部分，我们在此建立了不同的 Ndrg4 敲除（Ndrg4-/-）CRC 模型和原代肠神经系统（ENS）细胞与肠类器官的间接共培养，以确定 ENS 是否通过 NDRG4 影响肠道肿瘤发生。通过免疫染色和胃肠道蠕动（GI）测定，我们表明 Ndrg4 的缺失不会引发任何功能或形态学的 GI 异常。然而，结合体内、体外和定量蛋白质组学数据，我们发现 Ndrg4 敲低与肠道腺瘤的增大发展有关，而类器官的生长受到 Ndrg4 ENS 细胞分泌组的促进，该分泌组富含神经纤毛蛋白-1（Nidogen-1，NID1）和纤维连接蛋白-2（Fibulin-2，FBLN2）。此外，NID1 和 FBLN2 在肠神经元中表达，增强 CRC 细胞的迁移能力，并在人 CRC 分泌组中富集。因此，我们提供的证据表明，ENS 通过 Ndrg4 的缺失参与了结直肠癌的发病机制，ENS 衍生的 Nidogen-1 和 Fibulin-2 增强了结直肠的癌变过程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/a8fb86f882aa/EMBR-22-e51913-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/3bac575a7766/EMBR-22-e51913-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/616fc9627301/EMBR-22-e51913-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/4cd2b8b5099d/EMBR-22-e51913-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/d35285499166/EMBR-22-e51913-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/ae05c24af9e2/EMBR-22-e51913-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/a8fb86f882aa/EMBR-22-e51913-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/3bac575a7766/EMBR-22-e51913-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/b4e2da95e233/EMBR-22-e51913-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/616fc9627301/EMBR-22-e51913-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/4cd2b8b5099d/EMBR-22-e51913-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/d35285499166/EMBR-22-e51913-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/ae05c24af9e2/EMBR-22-e51913-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2313/8183412/a8fb86f882aa/EMBR-22-e51913-g002.jpg

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