de Marcondes Priscila Guimarães, Bastos Lilian Gonçalves, de-Freitas-Junior Julio Cesar Madureira, Rocha Murilo Ramos, Morgado-Díaz José Andrés
Cellular Biology Program, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ, 20230-051, Brazil.
Tumour Biol. 2016 Sep;37(9):12411-12422. doi: 10.1007/s13277-016-5120-0. Epub 2016 Jun 21.
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.
放射疗法广泛应用于晚期直肠肿瘤。然而，这种治疗后的肿瘤复发往往更具侵袭性，且预后较差。揭示控制这种复发的分子机制对于开发新的治疗方法至关重要。在本研究中，我们证明放疗会增加接受该治疗的结肠癌细胞存活后代的EphA4激活水平，并且这种激活促进了E-钙黏蛋白-EphA4复合物的内化，导致细胞间黏附破坏。此外，照射后细胞后代中的EphA4敲低降低了照射诱导的迁移和侵袭潜能以及金属蛋白酶活性。最后，我们证明细胞迁移和侵袭潜能受AKT和ERK1/2信号通路调节，其中ERK1/2活性依赖于EphA4。总之，我们的研究表明这些信号通路可能是治疗失败的原因，从而促进直肠癌放疗后的局部侵袭和转移。我们还推测EphA4是结直肠癌治疗的潜在治疗靶点。
