Correlation between TXNRD1/HO-1 Expression and the Histological Response to Neoadjuvant Chemoradiation Therapy in patients with Esophageal Squamous Cell Carcinoma

Abstract

BackgroundNrf2 signaling plays a pivotal role in antioxidant response, and its expression has been reported to increase in various human malignancies, including esophageal squamous cell carcinoma (ESCC). This also leads to resistance against chemotherapy and radiotherapy in patients. Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are proteins involved in this pathway that play key roles in antioxidant responses. However, the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), and the changes before and after chemoradiation therapy in patients with ESCC, remain unknown. MethodsThe proteins involved in the Nrf2 signaling pathway were immunolocalized in carcinoma cells in patients with ESCC undergoing NACRT with 5-fluorouracil and cisplatin followed by esophagectomy. The 8-OHdG levels were used to determine ROS levels in individual carcinoma cells. Fifty-two pre-operative endoscopic biopsy and fifty post-operative resected specimens were available for this study. Among these, 39 specimens were available for comparison of the results before and after NACRT. The changes in immunoreactivity before and after NACRT (Δ) were assessed. ResultsSignificant histological resistance to NACRT was observed in patients with high levels of Nrf2, TXNRD1, and HO-1 expression. Among pre-therapeutic biopsy specimens, the tumor reduction effect was significantly attenuated in those with high levels of Nrf2, TXNRD1, and HO-1 expression. TXNRD1Δ and HO-1Δ were both significantly higher, while 8-OHdGΔ was significantly lower in the ineffective (poor response) groups. In resected specimens, the overall survival was significantly lower in groups with high Nrf2, TXNRD1, HO-1, and HO-1Δ values. Disease-free survival was significantly lower in the groups with high expression of Nrf2, TXNRD1, HO-1, and Ki-67 and large values of HO-1Δ, and Ki-67Δ. ConclusionsThe results of this study indicate that high Nrf2, TXNRD1, and HO-1 expression in pre-therapeutic biopsy specimens could predict the histological response to NACRT, and their status in surgically resected specimens could predict clinical outcomes in patients with ESCC.