The expression of p‐p62 and nuclear Nrf2 in esophageal squamous cell carcinoma and association with radioresistance

BACKGROUND: The roles of p62‐Keap1‐Nrf2 pathway in the radioresistance of esophageal squamous cell carcinoma (ESCC) have not yet been revealed. This study aimed to clarify the expression and correlation of p‐p62 and nuclear Nrf2 and their association with radioresistance in ESCC. METHODS: This study included 164 cases of inoperable locally advanced ESCC. All patients received concurrent chemoradiotherapy (CCRT). Immunohistochemical staining was used to detect the expression of p‐p62 and nuclear Nrf2. The results were analyzed independently by two pathologists. RESULTS: There was no significant relationship between p‐p62 or nuclear Nrf2 and patients' clinical characteristics. Compared to patients with low expression of p‐p62, patients with high expression of p‐p62 showed lower objective response rate (ORR). Similarly, patients with high expression of nuclear Nrf2 exhibited lower ORR compared to those with low expression of nuclear Nrf2. The expression of p‐p62 was positively correlated with that of nuclear Nrf2. Moreover, the correlation coefficient between them was higher among patients showing no response to CCRT. Univariate analysis revealed that higher expression of p‐p62 or nuclear Nrf2 was significantly associated with poorer PFS and OS. Multivariate analysis indicated that the expression of nuclear Nrf2 and treatment response were independent prognostic factors for PFS. Sex, treatment response, expression of p‐p62 and nuclear Nrf2 were independent prognostic factors for OS. CONCLUSION: Higher expression of p‐p62 and nuclear Nrf2 are associated with lower ORR as well as poorer prognosis, which indicates that p62‐Keap1‐Nrf2 pathway might play an essential role in the radioresistance of ESCC. KEY POINTS: The expression of p‐p62 and nuclear Nrf2 in ESCC show a significant relationship with patients' responses to CCRT and influence the prognosis of ESCC. p62‐Keap1‐Nrf2 pathway might be a new target for radiosensitization in ESCC.