期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 32, 页码 E6603-E6612出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1706011114
关键词
neuroblastoma; Rho signaling; ROCK; personalized medicine; Wnt signaling
资金
- Swedish Childhood Cancer Foundation
- Swedish Cancer Foundation
- Swedish Research Council
- Eva och Oscars Ahrens Research Foundation
- Magnus Bergvall Foundation
- Mary Beve Foundation
- Marta and Gunnar V. Philipson Foundation
- Anna-Brita and Bo Castegren Memorial Foundation
- Sigurd and Elsa Goljes Memorial Foundation
- Swedish Foundation for Strategic Research
- Karolinska Institutet
- Stockholm County Council
- Cancer Research Foundations of Radiumhemmet
Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK) 2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3 beta-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.
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