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000294418 0247_ $$2ISSN$$a1756-9966
000294418 037__ $$aDKFZ-2024-02247
000294418 041__ $$aEnglish
000294418 082__ $$a610
000294418 1001_ $$aZucchini, Cinzia$$b0
000294418 245__ $$aROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity.
000294418 260__ $$aLondon$$bBioMed Central$$c2019
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000294418 520__ $$aThe 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.
000294418 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000294418 650_7 $$2Other$$aMetastasis
000294418 650_7 $$2Other$$aOsteosarcoma
000294418 650_7 $$2Other$$aROCK2
000294418 650_7 $$2Other$$aVerteporfin
000294418 650_7 $$2Other$$aYAP
000294418 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000294418 650_7 $$2NLM Chemicals$$aTranscription Factors
000294418 650_7 $$2NLM Chemicals$$aYAP-Signaling Proteins
000294418 650_7 $$2NLM Chemicals$$aYAP1 protein, human
000294418 650_7 $$00X9PA28K43$$2NLM Chemicals$$aVerteporfin
000294418 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aROCK2 protein, human
000294418 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$arho-Associated Kinases
000294418 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: genetics
000294418 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000294418 650_2 $$2MeSH$$aAdolescent
000294418 650_2 $$2MeSH$$aAnimals
000294418 650_2 $$2MeSH$$aBone Neoplasms: genetics
000294418 650_2 $$2MeSH$$aBone Neoplasms: metabolism
000294418 650_2 $$2MeSH$$aBone Neoplasms: pathology
000294418 650_2 $$2MeSH$$aBone Neoplasms: therapy
000294418 650_2 $$2MeSH$$aCell Line, Tumor
000294418 650_2 $$2MeSH$$aCell Movement
000294418 650_2 $$2MeSH$$aCell Proliferation
000294418 650_2 $$2MeSH$$aChild
000294418 650_2 $$2MeSH$$aDisease Models, Animal
000294418 650_2 $$2MeSH$$aFemale
000294418 650_2 $$2MeSH$$aHeterografts
000294418 650_2 $$2MeSH$$aHumans
000294418 650_2 $$2MeSH$$aImmunohistochemistry
000294418 650_2 $$2MeSH$$aKaplan-Meier Estimate
000294418 650_2 $$2MeSH$$aMice
000294418 650_2 $$2MeSH$$aOsteosarcoma: genetics
000294418 650_2 $$2MeSH$$aOsteosarcoma: metabolism
000294418 650_2 $$2MeSH$$aOsteosarcoma: pathology
000294418 650_2 $$2MeSH$$aOsteosarcoma: therapy
000294418 650_2 $$2MeSH$$aPrognosis
000294418 650_2 $$2MeSH$$aProtein Binding
000294418 650_2 $$2MeSH$$aRNA Interference
000294418 650_2 $$2MeSH$$aTranscription Factors: genetics
000294418 650_2 $$2MeSH$$aTranscription Factors: metabolism
000294418 650_2 $$2MeSH$$aVerteporfin: pharmacology
000294418 650_2 $$2MeSH$$aYAP-Signaling Proteins
000294418 650_2 $$2MeSH$$arho-Associated Kinases: genetics
000294418 650_2 $$2MeSH$$arho-Associated Kinases: metabolism
000294418 7001_ $$aManara, Maria Cristina$$b1
000294418 7001_ $$aCristalli, Camilla$$b2
000294418 7001_ $$aCarrabotta, Marianna$$b3
000294418 7001_ $$aGreco, Sara$$b4
000294418 7001_ $$aPinca, Rosa Simona$$b5
000294418 7001_ $$aFerrari, Cristina$$b6
000294418 7001_ $$aLanduzzi, Lorena$$b7
000294418 7001_ $$aPasello, Michela$$b8
000294418 7001_ $$aLollini, Pier-Luigi$$b9
000294418 7001_ $$aGambarotti, Marco$$b10
000294418 7001_ $$aDonati, Davide Maria$$b11
000294418 7001_ $$aScotlandi, Katia$$b12
000294418 773__ $$0PERI:(DE-600)2430698-8$$a10.1186/s13046-019-1506-3$$gVol. 38, no. 1, p. 503$$n1$$p503$$tJournal of experimental & clinical cancer research$$v38$$x0392-9078$$y2019
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