The Wnt5a receptors Ror1 and Ror2 exert opposite effects on the proliferation of melanoma cells.

CASTRO MV; BARBERO G; VILLANUEVA MB; MUÑOZ CONTRERAS I; LOPEZ BERGAMI P.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de BioCiencias; 2017

Sociedades de BioCiencias

Melanoma is the deadliest form of skin cancer and its incidencecontinues to increase, making it the fifth most frequent typeof tumor. In the past years, several molecular pathways involvedin melanoma development and progression have been uncovered.Wnt5a is a secreted glycoprotein that activates the non-canonicalWnt pathway and has been implicated in progression of severaltumor types including melanoma. Wnt5a activates various downstreamsignaling pathways upon binding of Fzd, Ryk or ROR1/2 receptors.Antibodies targeting ROR1 have been proposed as a newtherapeutical approach to inhibit Wnt signaling. The tyrosine kinasereceptors ROR1 and ROR2 play a key role in embryonic developmentbut their expression becomes undetectable in adulthood.However, the aberrant expression of these receptors has beenlinked to the progression of various types of cancer.The aim of the present project is to determine the role of ROR1and ROR2 on melanoma proliferation and the underlying molecularmechanisms. Overexpression of ROR1 was shown to increaseproliferation by 44,7% ± 6,6% (p <0,01). This effect was consistentwith a positive regulation of Akt, p65 and Cyclin D1. Western blotexperiments determined an increase of 62,46% (p <0,01), 296,18%(p <0,01) and 23,87% (p <0,05) in Akt, P-p65 and Cyclin D1 levels,respectively.On the other hand, ROR2 overexpression decreased proliferationby 22,38% ± 9,68% (p <0,01), which was accompanied by a negativeregulation of Akt, STAT3 and Cdk4. Western blot experimentsdetermined a decrease of 62,46% (p <0,01), 55,46% (p <0,01),33,67% (p <0,01) in P-Akt, P-STAT3 and Cdk4 levels, respectively.In addition, we observed an increase of 149% (p <0,01) in p21 levels.In summary, these results suggest an opposite role for thesereceptors. While ROR1 would favor proliferation of melanoma,ROR2 would slow it down. This result has important implicanciesfor the development and application of therapies against the Wntpathway in melanoma.