ROR1 contributes to melanoma cell growth and migration by regulating N-cadherin expression via the PI3K/Akt pathway
Natalia Brenda Fernández
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorDaniela Lorenzo
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría Elisa Picco
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorGastón Barbero
Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina
Search for more papers by this authorLeonardo Sebastián Dergan-Dylon
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría Paula Marks
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorHernán García-Rivello
Servicio de Anatomía Patológica, Hospital Italiano, Buenos Aires, Argentina
Search for more papers by this authorLiliana Gimenez
Instituto de Oncología Ángel Roffo, Buenos Aires, Argentina
Search for more papers by this authorVivian Labovsky
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorLuca Grumolato
INSERM U982, Institute for Research and Innovation in Biomedicine, University of Rouen, France
Search for more papers by this authorCorresponding Author
Pablo Lopez-Bergami
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina
Correspondence to: Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina (1405).
Search for more papers by this authorNatalia Brenda Fernández
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorDaniela Lorenzo
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría Elisa Picco
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorGastón Barbero
Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina
Search for more papers by this authorLeonardo Sebastián Dergan-Dylon
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría Paula Marks
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorHernán García-Rivello
Servicio de Anatomía Patológica, Hospital Italiano, Buenos Aires, Argentina
Search for more papers by this authorLiliana Gimenez
Instituto de Oncología Ángel Roffo, Buenos Aires, Argentina
Search for more papers by this authorVivian Labovsky
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Search for more papers by this authorLuca Grumolato
INSERM U982, Institute for Research and Innovation in Biomedicine, University of Rouen, France
Search for more papers by this authorCorresponding Author
Pablo Lopez-Bergami
Instituto de Medicina y Biología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimónides, CONICET, Buenos Aires, Argentina
Correspondence to: Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y Diagnóstico, Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina (1405).
Search for more papers by this authorAbstract
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.
Supporting Information
Additional supporting information may be found in the online version of this article at the publisher's web-site.
| Filename | Description |
|---|---|
| mc22426-sup-0001-SupFig-S1.tif4.5 MB |
Figure S1. Expression of ROR1 does not differ between primary and metastatic cell lines. |
| mc22426-sup-0002-SupFig-S2-part-1.tif10 MB |
Figure S2. Expression profiling of ROR1 and Wnt5a in melanoma cell lines. |
| mc22426-sup-0003-SupFig-S2-part-2.tif12.2 MB |
Figure Part 2. |
| mc22426-sup-0004-SupFig-S3.tif8.5 MB |
Figure S3. Neither ROR2 nor Wnt5a associates with survival. |
| mc22426-sup-0005-SupFig-S4.tif6.1 MB |
Figure S4. Silencing of ROR1 in A375 human melanoma cell line. |
| mc22426-sup-0006-SupFig-S5.tif4.5 MB |
Figure S5. Silencing of ROR1 in Lu1205 human melanoma cell line. |
| mc22426-sup-0007-SupFig-S6.tif6.2 MB |
Figure S6. Silencing of ROR1 in UACC903 human melanoma cell line. |
| mc22426-sup-0008-SupFig-S7.tif3.7 MB |
Figure S7. Overexpression of ROR1 in A375 melanoma cell line. |
| mc22426-sup-0009-SupFig-S8.tif5 MB |
Figure S8. Silencing of ROR1 decreases phosphorylation of Dvl-2 in Lu1205 cell line. |
| mc22426-sup-0010-SupFig-S9.tif4.9 MB |
Figure S9. ROR1 increases proliferation in A375 melanoma cells. |
| mc22426-sup-0011-SupFig-S10.tif9.2 MB |
Figure S10. ROR1 silencing inhibits anchorage-dependent and independent growth in Lu1205 melanoma cells. |
| mc22426-sup-0012-SupFig-S11.tif7 MB |
Figure S11. ROR1 affects motility of A375 melanoma cells. |
| mc22426-sup-0013-SupFig-S12.tif3.7 MB |
Figure S12. Silencing of ROR1 abrogates activation of RhoA/C. |
| mc22426-sup-0014-SupFig-S13.tif5.1 MB |
Figure S13. ROR1 regulates Akt3 but not Akt2. |
| mc22426-sup-0015-SupFig-S14.tif3 MB |
Figure S14. Wnt5a activates STAT3. |
| mc22426-sup-0016-SupFig-S15.tif4.5 MB |
Figure S15. Expression of ROR1 in primary and metastatic cell lines from Philadelphia dataset. |
| mc22426-sup-0017-SupTable-S1.pdf14.6 KB |
Table S1. Immunohistochemical analysis of ROR1 staining in melanoma tumor samples from Hospital Italiano. |
| mc22426-sup-0018-SupTable-S2.pdf14.1 KB |
Table S2. Immunohistochemical analysis of ROR1 staining in melanoma tumor samples from Instituto Roffo. |
| mc22426-sup-0019-SupTable-S3.pdf11.2 KB |
Table S3. Sequence of primers used for qRT-PCR. |
| mc22426-sup-0020-Suppmat.pdf382.7 KB | Supporting Information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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