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

Journal of Biomedical Science

Jérémie Nsengimana¹  Edith Illescas²  Gastón Alexis Barbero³  María Josefina Quezada³  María Victoria Castro³  María Belén Villanueva³  Pablo Lopez-Bergami⁴  Luca Grumolato⁵  Julia Newton-Bishop⁶ 

[1]Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, Newcastle upon Tyne, UK

[2]Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405, Buenos Aires, Argentina

[3]Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405, Buenos Aires, Argentina

[4]Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425, Buenos Aires, Argentina

[5]Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, 1405, Buenos Aires, Argentina

[6]Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1425, Buenos Aires, Argentina

[7]Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimonides, Hidalgo 775, 6th Floor, Lab 602., 1405, Buenos Aires, Argentina

[8]INSERM U982, Institute for Research and Innovation in Biomedicine, University of Rouen, 76183, Rouen, France

[9]Leeds Institute of Medical Research, LS2 9JT, Leeds, UK

关键词: ROR2;    Akt;    Melanoma;    Wnt5a;    Cell-cycle;    Proliferation;    Cyclins;    Breslow thickness;    Survival;   

DOI  :  10.1186/s12929-021-00776-w

来源: Springer

【 摘 要 】

BackgroundReceptor 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.MethodsGain 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.ResultsUnlike 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.ConclusionWe 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.

【 授权许可】

CC BY