Amphiregulin and Epiregulin confer radioresistance in esophageal squamous cell carcinoma through oxidative phosphorylation

Neoadjuvant chemoradiotherapy combines surgery has been the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) patients. However, up to 30-50% of nCRT patients can achieve pathological complete response (pCR) and long-term survival, while a considerable number of patients experience short-term recurrence or even progression disease. Therefore, to find out the biomarkers which can better and accurate predict chemoradiation efficacy and understanding the hidden mechanism is still urgently needed. Herein, we found that mitochondrial oxidative phosphorylation (OXPHOS) was involved in radioresistance of nCRT in ESCC patients. CEBPB/AREG/EREGE axis was responsible to affect radiosensitivity through OXPHOS. Either target mitochondrial OXPHOS or ERBB signal pathway effectively enhanced the radiosensitivity for ESCC cells. This study demonstrated the underlying mechanism for AREG/EREG/ERBB regulated OXPHOS involved in ESCC radiosensitivity and provided more opportunities to target vulnerable processes to improve ESCC radiation efficacy for clinic treatment.