EphA4-mediated signaling regulates the aggressive phenotype of irradiation survivor colorectal cancer cells.
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.
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
Priscila Guimarães
PG
de Marcondes
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
Lilian Gonçalves
LG
Bastos
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
Julio Cesar Madureira
JC
de-Freitas-Junior
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
Murilo Ramos
MR
Rocha
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil. jmorgado@inca.gov.br.
José Andrés
JA
Morgado-Díaz
D015703:Antigens, CD; D015820:Cadherins / Q000032:analysis; D015179:Colorectal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D017292:Doxazosin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D036122:Receptor, EphA4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D036122:Receptor, EphA4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D017292:Doxazosin
Colorectal cancer; E-cadherin; EphA4 receptor; Radiotherapy; Signaling pathways