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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Prognostic value and functional role of ROCK2 in pediatric Ewing sarcoma

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Author(s):
Vieira, Gabriela Maciel [1] ; Roberto, Gabriela Molinari [2] ; Lira, Regia Caroline [3] ; Engel, Edgard Eduard [4] ; Tone, Luiz Gonzaga [4] ; Brassesco, Maria Sol [5]
Total Authors: 6
Affiliation:
[1] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Genet, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Reg Blood Ctr, BR-14040901 Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biomech Med & Rehabil Locomotor Syst, BR-14040901 Ribeirao Preto, SP - Brazil
[4] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Pediat, Ribeirao Preto Sch Med, BR-14040901 Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biol, 3900 Av Bandeirantes, BR-14040901 Ribeirao Preto, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Oncology Letters; v. 15, n. 2, B, p. 2296-2304, FEB 2018.
Web of Science Citations: 0
Abstract

Ewing's sarcoma (EWS) is a highly aggressive bone cancer that affects children and adolescents. Despite advances in multimodal management, 5-year event-free survival rates for patients presenting with metastases at diagnosis remain at 25%. As key regulators of actin organization, the Rho-associated coiled-coil containing protein kinases, ROCK1 and ROCK2, have been associated with cancer dissemination and poorer prognosis. Recently, in vitro data indicating ROCK2 as a molecular target for the treatment of EWS has been presented. Nonetheless, a deeper exploration of the contribution of this kinase dysregulation in EWS is still necessary. In this regard, the present study aimed to evaluate the expression of ROCK1 and ROCK2 in 23 pediatric tumor samples and to verify the prospect of using their pharmacological inhibition through functional assays. Our results showed positive immunostaining for ROCK1 and ROCK2 in the majority samples (75 and 65%, respectively). A significantly increased risk of incomplete remission in patients with positive immunostaining for ROCK2 was found (P=0.026), though no correlations with other prognostic features (huvos classification, FLII/EWS status, relapse, metastasis or death) were observed. Associations with survival were merely suggestive. Apparent protein expression of both kinases was also found in EWS cell lines (SK-ES-1 and RD-ES). Treatments with selective ROCK inhibitors did not alter cell viability or migration in vitro. However, a significant increase in invasion was observed after treatment with SR3677 (ROCK2 inhibitor) and hydroxyfasudil (pan-inhibitor). Consequently, even though the majority of EWS samples included in our study showed positivity for ROCK1 and ROCK2, the lack of significant associations with prognosis and absence of appropriate responses to their inhibition in vitro does not support their prospective use as therapeutic targets for the treatment of this metastatic tumor. Larger cohort studies might provide more evidence on whether there is a specific role of ROCK kinases in EWS physiopathology. (AU)

FAPESP's process: 14/07118-0 - Effects of rock kinase inhibition in the invasive potential of Ewing Sarcoma cell lines
Grantee:Gabriela Maciel Vieira
Support type: Scholarships in Brazil - Master
FAPESP's process: 14/03877-3 - Evaluation of rock kinases and their interaction with microRNAs in bone sarcomas of childhood: implications for tumor progression and invasion
Grantee:María Sol Brassesco Annichini
Support type: Regular Research Grants