TY  - JOUR
AU  - Zucchini, Cinzia
AU  - Manara, Maria Cristina
AU  - Cristalli, Camilla
AU  - Carrabotta, Marianna
AU  - Greco, Sara
AU  - Pinca, Rosa Simona
AU  - Ferrari, Cristina
AU  - Landuzzi, Lorena
AU  - Pasello, Michela
AU  - Lollini, Pier-Luigi
AU  - Gambarotti, Marco
AU  - Donati, Davide Maria
AU  - Scotlandi, Katia
TI  - ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity.
JO  - Journal of experimental & clinical cancer research
VL  - 38
IS  - 1
SN  - 0392-9078
CY  - London
PB  - BioMed Central
M1  - DKFZ-2024-02247
SP  - 503
PY  - 2019
AB  - The treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling.The effects of ROCK2 depletion on metastasis were studied in NOD Scid gamma (NSG) mice injected with U-2OS cells in which ROCK2 expression had been stably silenced. Functional studies were performed in vitro in human U-2OS cells and in three novel cell lines derived from patient-derived xenografts (PDXs) by using standard methods to evaluate malignancy parameters and signaling transduction. The nuclear immunostaining of YAP and the evaluation of its downstream targets Cysteine Rich Angiogenic Inducer 6, Connective Tissue Growth Factor and Cyclin D1 by quantitative PCR were performed to analyze YAP activity. The effect of the expression and activity of ROCK2 and YAP on tumor progression was analyzed in 175 OS primary tumors.The silencing of ROCK2 markedly reduced tumor growth and completely abolished the metastatic ability of U-2OS cells. The depletion of ROCK2, either by pharmacological inhibition or silencing, induced a dose- and time-dependent reduction in the nuclear expression and transcriptional activity of YAP. The nuclear expression of YAP was observed in 80/175 (46
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adolescent
KW  - Animals
KW  - Bone Neoplasms: genetics
KW  - Bone Neoplasms: metabolism
KW  - Bone Neoplasms: pathology
KW  - Bone Neoplasms: therapy
KW  - Cell Line, Tumor
KW  - Cell Movement
KW  - Cell Proliferation
KW  - Child
KW  - Disease Models, Animal
KW  - Female
KW  - Heterografts
KW  - Humans
KW  - Immunohistochemistry
KW  - Kaplan-Meier Estimate
KW  - Mice
KW  - Osteosarcoma: genetics
KW  - Osteosarcoma: metabolism
KW  - Osteosarcoma: pathology
KW  - Osteosarcoma: therapy
KW  - Prognosis
KW  - Protein Binding
KW  - RNA Interference
KW  - Transcription Factors: genetics
KW  - Transcription Factors: metabolism
KW  - Verteporfin: pharmacology
KW  - YAP-Signaling Proteins
KW  - rho-Associated Kinases: genetics
KW  - rho-Associated Kinases: metabolism
KW  - Metastasis (Other)
KW  - Osteosarcoma (Other)
KW  - ROCK2 (Other)
KW  - Verteporfin (Other)
KW  - YAP (Other)
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - YAP-Signaling Proteins (NLM Chemicals)
KW  - YAP1 protein, human (NLM Chemicals)
KW  - Verteporfin (NLM Chemicals)
KW  - ROCK2 protein, human (NLM Chemicals)
KW  - rho-Associated Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:31878963
C2  - pmc:PMC6933701
DO  - DOI:10.1186/s13046-019-1506-3
UR  - https://inrepo02.dkfz.de/record/294418
ER  -