Rodrigo Guedes Hakime, Luís Fernando Peinado Nagano, María Sol Brassesco
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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.
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.