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EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells

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Tumor Biology

Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil

    Priscila Guimarães de Marcondes, Lilian Gonçalves Bastos, Julio Cesar Madureira de-Freitas-Junior, Murilo Ramos Rocha & José Andrés Morgado-Díaz

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  1. Priscila Guimarães de Marcondes
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  2. Lilian Gonçalves Bastos
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Correspondence to José Andrés Morgado-Díaz.

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Fig. 1 Supplemental

Total lysated from HT-29 F1 Cont and F1 5Gy were obtained and analyzed by immunoblotting for p-AKT and p-ERK. F1 5Gy cells show increased levels of these kinases comparing with F1 Cont cells. Bar graphs are plotted as a fold change of protein expression where non-treated cells (F1 Cont = 1). α-Tubulin was used as a loading control. Data are representative of two independent experiments (GIF 6 kb)

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de Marcondes, P.G., Bastos, L.G., de-Freitas-Junior, J.C.M. et al. EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells. Tumor Biol. 37, 12411–12422 (2016). https://doi.org/10.1007/s13277-016-5120-0

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