Effect Of EGFR Signaling On Radiosensitivity Of Esophageal Cancer Cells

Esophageal cancer is a common cancer in China that is reported to have an incidence rate of 477.9 per 100,000 in 2015(Chen et al.,2016).Surgery is the primary treatment for esophageal cancer,radiotherapy and chemotherapy are also widely used in combination based on the clinical stage.Radiotherapy is usually combined with chemotherapy and targeted therapy in the clinic(Goense et al.,2016;Mariette et al.,2007;Ohashi et al.,2015).However,the radiotherapeutic effect remains unsatisfactory,and radioresistance is highly common in clinical treatment,leading to possible treatment failure.Therefore,strategies to increase radiosensitivity are urgently needed.Our previous data showed that patients of esophageal squamous cell carcinoma with high EGFR expression could benefit from postoperative radiotherapy,while others with EGFR low expression will not.In this study,we try to investigate the molecular mechanism of EGFR signaling pathway on the radiosensitivity in esophageal squamous cell carcinoma.Radiation could inhibit the activation of EGFR signaling pathway in esophageal squamous cancer cells,and also induce the nuclear translocation of EGFR.But in EGFR-overexpressed ESCC cells,the sensitivity to radiation was significantly enhanced.When nuclear translocation of EGFR was blocked,the radiosensitivity was further enhanced.Our results indicated that EGFR-overexpressed ESCC cells were more sensitive to radiation,and blocking the nuclear translocation of EGFR could significantly enhance radiosensitivity of ESCC cells.Survivin could be upregulated by 8Gy radiation in ESCC cells,while in EGFR-overexpressed cells,the upregulation of Survivin induced by radiation was inhibited.The result indicated that inhibition of Survivin might contribute to the radiosensitization of EGFR-overexpressed ESCC cells.Subsequently,we treated cells with YM155,a Survivin inhibitor,to investigate whether it had radiosensitization effects on ESCC cells.The results showed that YM155 could inhibit the upregulation of Survivin induced by radiation in all four ESCC cell lines,but the efficacy of radiosensitization varied in different cell lines.Radiation induced senescence in KYSE150 and KYSE410 cells,and the combination with YM155 inhibited senescence and promoted apoptosis of ESCC cells,thereby enhancing radiosensitivity.Combination with YM155 and radiation delayed the growth of KYSE150 xenografts in nude mice by switching radiation induced senescence to apoptosis.When p21 was inhibited in KYSE150 cells,radiation did not induce senescence,and the radiosensitization of YM155 was also attenuated.In KYSE510 and KYSE180 cells,radiation did not induce senescence,and YM155 could not enhance the radiosensitivity.In summary,radiation could inhibit the activation of EGFR signaling pathway and induce nuclear translocation of EGFR in ESCC cells.But EGFR-overexpressed ESCC cells were more sensitive to radiation,and the inhibition of Survivin might contribute to the radiosensitization in EGFR-overexpressed cells.Suppression of Survivin by YM155 might sensitize ESCC cells to radiation by switching radiation-induced senescence to apoptosis.The major determinant of radiosensitization by YM155 might be the induction of senescence by radiation.