Home > Institute Collections > W500 > ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity. > print

001     294418
005     20241107161047.0
024 7 _ |a 10.1186/s13046-019-1506-3
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024 7 _ |a pmc:PMC6933701
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024 7 _ |a 0392-9078
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024 7 _ |a 1756-9966
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037 _ _ |a DKFZ-2024-02247
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Zucchini, Cinzia
|b 0
245 _ _ |a ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity.
260 _ _ |a London
|c 2019
|b BioMed Central
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1730990935_23508
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336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a 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%) tumor samples and was significantly correlated with worse patient prognosis and a higher likelihood of metastasis and death. The use of verteporfin, a molecule that specifically inhibits the TEAD-YAP association, remarkably impaired the growth and migration of OS cells in vitro. Moreover to inhibiting YAP activity, our findings indicate that verteporfin also affects the ROCK2 protein and its functions.We describe the functional connection between ROCK2 and YAP in the regulation of OS cell migration and metastasis formation. These data provide support for the use of verteporfin as a possible therapeutic option to prevent OS cell dissemination.
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a Metastasis
|2 Other
650 _ 7 |a Osteosarcoma
|2 Other
650 _ 7 |a ROCK2
|2 Other
650 _ 7 |a Verteporfin
|2 Other
650 _ 7 |a YAP
|2 Other
650 _ 7 |a Adaptor Proteins, Signal Transducing
|2 NLM Chemicals
650 _ 7 |a Transcription Factors
|2 NLM Chemicals
650 _ 7 |a YAP-Signaling Proteins
|2 NLM Chemicals
650 _ 7 |a YAP1 protein, human
|2 NLM Chemicals
650 _ 7 |a Verteporfin
|0 0X9PA28K43
|2 NLM Chemicals
650 _ 7 |a ROCK2 protein, human
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a rho-Associated Kinases
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 2 |a Adaptor Proteins, Signal Transducing: genetics
|2 MeSH
650 _ 2 |a Adaptor Proteins, Signal Transducing: metabolism
|2 MeSH
650 _ 2 |a Adolescent
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Bone Neoplasms: genetics
|2 MeSH
650 _ 2 |a Bone Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Bone Neoplasms: pathology
|2 MeSH
650 _ 2 |a Bone Neoplasms: therapy
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Cell Movement
|2 MeSH
650 _ 2 |a Cell Proliferation
|2 MeSH
650 _ 2 |a Child
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Heterografts
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Immunohistochemistry
|2 MeSH
650 _ 2 |a Kaplan-Meier Estimate
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Osteosarcoma: genetics
|2 MeSH
650 _ 2 |a Osteosarcoma: metabolism
|2 MeSH
650 _ 2 |a Osteosarcoma: pathology
|2 MeSH
650 _ 2 |a Osteosarcoma: therapy
|2 MeSH
650 _ 2 |a Prognosis
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
650 _ 2 |a RNA Interference
|2 MeSH
650 _ 2 |a Transcription Factors: genetics
|2 MeSH
650 _ 2 |a Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Verteporfin: pharmacology
|2 MeSH
650 _ 2 |a YAP-Signaling Proteins
|2 MeSH
650 _ 2 |a rho-Associated Kinases: genetics
|2 MeSH
650 _ 2 |a rho-Associated Kinases: metabolism
|2 MeSH
700 1 _ |a Manara, Maria Cristina
|b 1
700 1 _ |a Cristalli, Camilla
|b 2
700 1 _ |a Carrabotta, Marianna
|b 3
700 1 _ |a Greco, Sara
|b 4
700 1 _ |a Pinca, Rosa Simona
|b 5
700 1 _ |a Ferrari, Cristina
|b 6
700 1 _ |a Landuzzi, Lorena
|b 7
700 1 _ |a Pasello, Michela
|b 8
700 1 _ |a Lollini, Pier-Luigi
|b 9
700 1 _ |a Gambarotti, Marco
|b 10
700 1 _ |a Donati, Davide Maria
|b 11
700 1 _ |a Scotlandi, Katia
|b 12
773 _ _ |a 10.1186/s13046-019-1506-3
|g Vol. 38, no. 1, p. 503
|0 PERI:(DE-600)2430698-8
|n 1
|p 503
|t Journal of experimental & clinical cancer research
|v 38
|y 2019
|x 0392-9078
856 4 _ |u https://inrepo02.dkfz.de/record/294418/files/s13046-019-1506-3.pdf
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