ROCK2 Downregulation in Pediatric Medulloblastoma Increases Migration and Predicts the Involvement of SHH Non-canonical Signaling.

IF 2.5 3区 工程技术 Q2 BIOLOGY
Yale Journal of Biology and Medicine Pub Date : 2025-03-31 eCollection Date: 2025-03-01 DOI:10.59249/QTVT7676
Rodrigo Guedes Hakime, Luís Fernando Peinado Nagano, María Sol Brassesco
{"title":"ROCK2 Downregulation in Pediatric Medulloblastoma Increases Migration and Predicts the Involvement of SHH Non-canonical Signaling.","authors":"Rodrigo Guedes Hakime, Luís Fernando Peinado Nagano, María Sol Brassesco","doi":"10.59249/QTVT7676","DOIUrl":null,"url":null,"abstract":"<p><p>The participation of the Rho-associated protein kinases (ROCK1 and 2) in the regulation of actin cytoskeleton organization, cell adhesion, motility, and gene expression has been extensively investigated in many tumors of different histology. However, their pathogenic roles in medulloblastoma (MB) remain understudied, demanding a deeper appreciation of their participation in cancer cell dissemination and tumor progression. Herein, we show that <i>ROCK2</i> is downregulated in MB tumor samples and functionally increases migration of cell lines belonging to the SHH subgroup. A comprehensive comparative bioinformatic scrutiny of differentially expressed genes within a list of ROCK2 candidate substrates, uncovered a network of 21 dysregulated genes from which <i>DYPSL3</i> (dihydropyrimidinase-related protein 3) denoted a strong positive correlation. Enrichment analysis revealed SHH/RHOA/ROCK2/DYPSL3 as top hub genes and the intersection between two biological processes of most importance in MB: actin cytoskeleton remodeling and neuron development. Of note, evidence shows that both ROCK2 and DYPSL3, interact with RHOA and in many tumor types they act as tumor suppressors, mitigating cell spreading. Alternatively, their impaired activity leads to undifferentiated phenotypes and inappropriate cytoskeletal dynamics affecting cell shape, attachment to the extracellular matrix, and cell movement. In parallel, cell motility is considered a prototypical non-canonical response to SHH mediated by RHOA. Therefore, we propose a model in which the interplay between these pathways may lead to a perturbation of proper cytoskeletal dynamics that underpins cell migration.</p>","PeriodicalId":48617,"journal":{"name":"Yale Journal of Biology and Medicine","volume":"98 1","pages":"3-19"},"PeriodicalIF":2.5000,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899262/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Yale Journal of Biology and Medicine","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.59249/QTVT7676","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The participation of the Rho-associated protein kinases (ROCK1 and 2) in the regulation of actin cytoskeleton organization, cell adhesion, motility, and gene expression has been extensively investigated in many tumors of different histology. However, their pathogenic roles in medulloblastoma (MB) remain understudied, demanding a deeper appreciation of their participation in cancer cell dissemination and tumor progression. Herein, we show that ROCK2 is downregulated in MB tumor samples and functionally increases migration of cell lines belonging to the SHH subgroup. A comprehensive comparative bioinformatic scrutiny of differentially expressed genes within a list of ROCK2 candidate substrates, uncovered a network of 21 dysregulated genes from which DYPSL3 (dihydropyrimidinase-related protein 3) denoted a strong positive correlation. Enrichment analysis revealed SHH/RHOA/ROCK2/DYPSL3 as top hub genes and the intersection between two biological processes of most importance in MB: actin cytoskeleton remodeling and neuron development. Of note, evidence shows that both ROCK2 and DYPSL3, interact with RHOA and in many tumor types they act as tumor suppressors, mitigating cell spreading. Alternatively, their impaired activity leads to undifferentiated phenotypes and inappropriate cytoskeletal dynamics affecting cell shape, attachment to the extracellular matrix, and cell movement. In parallel, cell motility is considered a prototypical non-canonical response to SHH mediated by RHOA. Therefore, we propose a model in which the interplay between these pathways may lead to a perturbation of proper cytoskeletal dynamics that underpins cell migration.

Rho相关蛋白激酶(ROCK1和ROCK2)参与肌动蛋白细胞骨架组织、细胞粘附、运动和基因表达的调控已在许多不同组织学的肿瘤中得到广泛研究。然而,它们在髓母细胞瘤(MB)中的致病作用仍未得到充分研究,因此需要更深入地了解它们在癌细胞扩散和肿瘤进展中的参与情况。在本文中,我们发现ROCK2在MB肿瘤样本中下调,并在功能上增加了属于SHH亚组的细胞系的迁移。通过对ROCK2候选底物列表中差异表达基因进行全面的生物信息学比较研究,我们发现了一个由21个失调基因组成的网络,其中DYPSL3(二氢嘧啶酶相关蛋白3)与这些基因有很强的正相关性。富集分析显示,SHH/RHOA/ROCK2/DYPSL3 是最重要的枢纽基因,也是 MB 中两个最重要的生物过程:肌动蛋白细胞骨架重塑和神经元发育的交叉点。值得注意的是,有证据表明,ROCK2 和 DYPSL3 与 RHOA 相互作用,在许多肿瘤类型中,它们是肿瘤抑制因子,能减轻细胞扩散。或者,它们的活性受损会导致未分化表型和不适当的细胞骨架动力学,影响细胞形状、与细胞外基质的附着以及细胞运动。与此同时,细胞运动被认为是由 RHOA 介导的对 SHH 的非典型反应。因此,我们提出了一个模型,在该模型中,这些途径之间的相互作用可能会导致适当的细胞骨架动力学受到干扰,而细胞骨架动力学是细胞迁移的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Yale Journal of Biology and Medicine
Yale Journal of Biology and Medicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.00
自引率
0.00%
发文量
41
期刊介绍: The Yale Journal of Biology and Medicine (YJBM) is a graduate and medical student-run, peer-reviewed, open-access journal dedicated to the publication of original research articles, scientific reviews, articles on medical history, personal perspectives on medicine, policy analyses, case reports, and symposia related to biomedical matters. YJBM is published quarterly and aims to publish articles of interest to both physicians and scientists. YJBM is and has been an internationally distributed journal with a long history of landmark articles. Our contributors feature a notable list of philosophers, statesmen, scientists, and physicians, including Ernst Cassirer, Harvey Cushing, Rene Dubos, Edward Kennedy, Donald Seldin, and Jack Strominger. Our Editorial Board consists of students and faculty members from Yale School of Medicine and Yale University Graduate School of Arts & Sciences. All manuscripts submitted to YJBM are first evaluated on the basis of scientific quality, originality, appropriateness, contribution to the field, and style. Suitable manuscripts are then subject to rigorous, fair, and rapid peer review.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信