ROR1 contributes to melanoma cell growth and migration by regulating N-cadherin expression via the PI3K/Akt pathway.
The Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is primarily expressed by neural crest cells during embryogenesis. Following a complete downregulation after birth, ROR1 was shown to re-express in various types of cancers. Little is known about ROR1 expression and function in melanoma. Here we show that ROR1 is aberrantly expressed in both melanoma cell lines and tumors and that its expression associates with poor Post-Recurrence Survival of melanoma. Using gain- and loss-of-function approaches we found that ROR1 enhances both anchorage-dependent and -independent growth of melanoma cells. In addition, ROR1 decreases cell adhesion and increases cell motility and migration. Mechanistically, ROR1 was found to induce upregulation of Akt and the mesenquimal markers N-cadherin and vimentin. The regulation of N-cadherin by ROR1 relies on both Akt dependent and independent mechanisms. ROR1 does not affect Wnt canonical pathway but was found to be engaged in a positive feedback loop with Wnt5a. In summary, we show that ROR1 contributes to melanoma progression and is a candidate biomarker of poor prognosis. Although further studies are needed to confirm this possibility, the present work indicates that ROR1 is a good prospective target for melanoma cancer therapy. © 2015 Wiley Periodicals, Inc.
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Natalia Brenda
NB
Fernández
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Daniela
D
Lorenzo
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
María Elisa
ME
Picco
Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina.
Gastón
G
Barbero
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Leonardo Sebastián
LS
Dergan-Dylon
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
María Paula
MP
Marks
Servicio de Anatomía Patológica, Hospital Italiano, Buenos Aires, Argentina.
Hernán
H
García-Rivello
Instituto de Oncología Ángel Roffo, Buenos Aires, Argentina.
Liliana
L
Gimenez
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Vivian
V
Labovsky
INSERM U982, Institute for Research and Innovation in Biomedicine, University of Rouen, France.
Luca
L
Grumolato
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. pablobergami@gmail.com.|Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina. pablobergami@gmail.com.
Pablo
P
Lopez-Bergami
D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D051057:Proto-Oncogene Proteins c-akt
Akt; N-cadherin; ROR1; melanoma; migration