EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells
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Radiotherapy is widely used for advanced rectal tumors. However, tumor recurrence after this treatment tends to be more aggressive and is associated with a poor prognosis. Uncovering the molecular mechanism that controls this recurrence is essential for developing new therapeutic applications. In the present study, we demonstrated that radiation increases the EphA4 activation level of the survivor progeny of colorectal cancer cells submitted to this treatment and that such activation promoted the internalization of a complex E-cadherin-EphA4, inducing cell–cell adhesion disruption. Moreover, EphA4 knockdown in the progeny of irradiated cells reduced the migratory and invasive potentials and metalloprotease activity induced by irradiation. Finally, we demonstrated that the cell migration and invasion potential were regulated by AKT and ERK1/2 signaling, with the ERK1/2 activity being dependent on EphA4. In summary, our study demonstrates that these signaling pathways could be responsible for the therapeutic failure, thereby promoting local invasion and metastasis in rectal cancer after radiotherapy. We also postulate that EphA4 is a potential therapeutic target for colorectal cancer treatment.
KeywordsEphA4 receptor E-cadherin Signaling pathways Colorectal cancer Radiotherapy
This study was sponsored by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Coordenação de Aperfeiçõamento de Pessoal de Nível Superior (CAPES), Ministério da Saúde – Brasil, Fundação Carlos Chagas Filho de Amparo á Pesquisa do Estado de Rio de Janeiro (FAPERJ), and Instituto Nacional de Ciência e Tecnologia em Câncer (573806/2008-0 and 170.026/2008). We are grateful to the Centro Nacional de Bioimagem (CENABIO) for the use of the super-resolution microscopy facility. This text was reviewed by American Journal Experts.
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