ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation

Abstract Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function st...

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Autores principales:	María Victoria Castro, Gastón Alexis Barbero, María Belén Villanueva, Luca Grumolato, Jérémie Nsengimana, Julia Newton-Bishop, Edith Illescas, María Josefina Quezada, Pablo Lopez-Bergami
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	ROR2 Akt Melanoma Wnt5a Cell-cycle Proliferation Medicine R
Acceso en línea:	https://doaj.org/article/4aa18ad8bb6d4dfa887f300feb49a3f7
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spelling	oai:doaj.org-article:4aa18ad8bb6d4dfa887f300feb49a3f72021-11-14T12:16:03ZROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation10.1186/s12929-021-00776-w1423-0127https://doaj.org/article/4aa18ad8bb6d4dfa887f300feb49a3f72021-11-01T00:00:00Zhttps://doi.org/10.1186/s12929-021-00776-whttps://doaj.org/toc/1423-0127Abstract Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Results Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. Conclusion We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.María Victoria CastroGastón Alexis BarberoMaría Belén VillanuevaLuca GrumolatoJérémie NsengimanaJulia Newton-BishopEdith IllescasMaría Josefina QuezadaPablo Lopez-BergamiBMCarticleROR2AktMelanomaWnt5aCell-cycleProliferationMedicineRENJournal of Biomedical Science, Vol 28, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ROR2 Akt Melanoma Wnt5a Cell-cycle Proliferation Medicine R
spellingShingle	ROR2 Akt Melanoma Wnt5a Cell-cycle Proliferation Medicine R María Victoria Castro Gastón Alexis Barbero María Belén Villanueva Luca Grumolato Jérémie Nsengimana Julia Newton-Bishop Edith Illescas María Josefina Quezada Pablo Lopez-Bergami ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
description	Abstract Background Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a Wnt5a receptor aberrantly expressed in cancer that was shown to either suppress or promote carcinogenesis in different tumor types. Our goal was to study the role of ROR2 in melanoma. Methods Gain and loss-of-function strategies were applied to study the biological function of ROR2 in melanoma. Proliferation assays, flow cytometry, and western blotting were used to evaluate cell proliferation and changes in expression levels of cell-cycle and proliferation markers. The role of ROR2 in tumor growth was assessed in xenotransplantation experiments followed by immunohistochemistry analysis of the tumors. The role of ROR2 in melanoma patients was assessed by analysis of clinical data from the Leeds Melanoma Cohort. Results Unlike previous findings describing ROR2 as an oncogene in melanoma, we describe that ROR2 prevents tumor growth by inhibiting cell-cycle progression and the proliferation of melanoma cells. The effect of ROR2 is mediated by inhibition of Akt phosphorylation and activity which, in turn, regulates the expression, phosphorylation, and localization of major cell-cycle regulators including cyclins (A, B, D, and E), CDK1, CDK4, RB, p21, and p27. Xenotransplantation experiments demonstrated that ROR2 also reduces proliferation in vivo, resulting in inhibition of tumor growth. In agreement with these findings, a higher ROR2 level favors thin and non-ulcerated primary melanomas with reduced mitotic rate and better prognosis. Conclusion We conclude that the expression of ROR2 slows down the growth of primary tumors and contributes to prolonging melanoma survival. Our results demonstrate that ROR2 has a far more complex role than originally described.
format	article
author	María Victoria Castro Gastón Alexis Barbero María Belén Villanueva Luca Grumolato Jérémie Nsengimana Julia Newton-Bishop Edith Illescas María Josefina Quezada Pablo Lopez-Bergami
author_facet	María Victoria Castro Gastón Alexis Barbero María Belén Villanueva Luca Grumolato Jérémie Nsengimana Julia Newton-Bishop Edith Illescas María Josefina Quezada Pablo Lopez-Bergami
author_sort	María Victoria Castro
title	ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
title_short	ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
title_full	ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
title_fullStr	ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
title_full_unstemmed	ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation
title_sort	ror2 has a protective role in melanoma by inhibiting akt activity, cell-cycle progression, and proliferation
publisher	BMC
publishDate	2021
url	https://doaj.org/article/4aa18ad8bb6d4dfa887f300feb49a3f7
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ROR2 has a protective role in melanoma by inhibiting Akt activity, cell-cycle progression, and proliferation

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