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卡利林-RAC 控制 ADRN 型神经母细胞瘤的核迁移。

Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma.

机构信息

Department of Neuroblastoma Genomics, Hopp-Children's Cancer Center at the (NCT) Nationales Centrum für Tumorerkrankungen Heidelberg (KiTZ), Heidelberg, Germany

Department of Neuroblastoma Genomics, Hopp-Children's Cancer Center at the (NCT) Nationales Centrum für Tumorerkrankungen Heidelberg (KiTZ), Heidelberg, Germany.

出版信息

Life Sci Alliance. 2021 Mar 3;4(5). doi: 10.26508/lsa.201900332. Print 2021 May.

DOI:10.26508/lsa.201900332
PMID:33658318
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8017594/
Abstract

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

摘要

神经母细胞瘤的迁移倾向受细胞身份的影响，但背后的机制仍不清楚。通过 RNAi 和延时成像，我们表明 ADRN 型 NB 细胞表现出 Rac1 和 kalirin 依赖性核动力（NUC）迁移，这依赖于神经元迁移的几个整体组成部分。Rac1 和 kalirin-GEF1 抑制剂对 NUC 迁移的抑制不会妨碍细胞增殖和 ADRN 身份。使用三种临床相关的表达二分法，我们揭示了 Rac1 和 kalirin-GEF1 抑制的 ADRN 型 NB 细胞中上调的大多数 mRNAs 与低风险特征相关。计算分析表明，在整体基因集匮乏的情况下，Rac1 和 kalirin-GEF1 抑制的 ADRN 型细胞中的上调组是一批富含 AU 元件的 mRNAs，这表明 NUC 迁移和 mRNA 稳定性之间存在联系。基于基因集富集分析的脆弱性搜索揭示了 Rac1 和 kalirin-GEF1 抑制的 ADRN 型 NB 细胞中的潜在弱点，包括 H3K27 和 DNA 甲基转移酶的活性。总之，这些数据支持将 NUC 抑制剂引入癌症治疗研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/b7bed80a26df/LSA-2019-00332_FigS11.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/b7bed80a26df/LSA-2019-00332_FigS11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/68743ba4956c/LSA-2019-00332_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/63b88044f746/LSA-2019-00332_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/6f7259cdea88/LSA-2019-00332_Fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/c17743cd16e7/LSA-2019-00332_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/967f6565a487/LSA-2019-00332_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/45b3455e1313/LSA-2019-00332_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/a54f892d6202/LSA-2019-00332_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/72344b3917e1/LSA-2019-00332_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/29278e2d30eb/LSA-2019-00332_FigS8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/68dd1d79a8f5/LSA-2019-00332_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/82377cdf304a/LSA-2019-00332_FigS9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/acbd8abb7c5c/LSA-2019-00332_FigS10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/7c6c134f418b/LSA-2019-00332_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d65/8017594/b7bed80a26df/LSA-2019-00332_FigS11.jpg

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