Abstract
BackgroundThioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown.MethodsProteins involved in the Nrf2 pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The 8-hydroxydeoxyguanosine (8-OHdG) levels were used to quantify reactive oxygen species. The changes in immunoreactivity before and after NACRT (Δ) were assessed.ResultsTumor reduction following NACRT was significantly attenuated in pre-therapeutic biopsy specimens associated with high HO-1 status. TXNRD1Δ, HO-1Δ, and 8-OHdGΔ were significantly different in the ineffective and effective groups. The overall survival was significantly lower in high Nrf2 and TXNRD1 groups. In addition, high TXNRD1 expression was an independent prognostic factor in the multivariate analysis of overall survival.ConclusionsThe study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients.
Highlights
Esophageal squamous cell carcinoma (ESCC) represents the majority of esophageal cancer cases in Japan and Asia [1]
In this study, we aimed to investigate the followings in esophageal squamous cell carcinoma (ESCC) patients: (1) predict neoadjuvant chemoradiation therapy (NACRT) efficacy and clinical outcomes/prognosis according to the status of Thioredoxin reductase 1 (TXNRD1)/heme oxygenase-1 (HO-1) in pre-NACRT endoscopic biopsy specimens and (2) examine the correlation between NACRT resistance and the difference of antioxidant protein expression in pre- and post-NACRT specimens
TXNRD1Δ, HO-1Δ, and 8-OhdGΔ were significantly associated with therapeutic efficacy
Summary
Esophageal squamous cell carcinoma (ESCC) represents the majority of esophageal cancer cases in Japan and Asia [1]. Thioredoxin reductase 1 (TXNRD1) and heme oxygenase-1 (HO-1) are both involved in the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and play key roles in antioxidant responses. In patients with esophageal squamous cell carcinoma (ESCC), the correlation between the expression of these two proteins and the therapeutic response to neoadjuvant chemoradiation therapy (NACRT), as well as the difference in their expression after chemoradiotherapy, remains unknown. Methods Proteins involved in the Nrf pathway were immunolocalized in carcinoma cells in ESCC patients on NACRT with 5-fluorouracil and cisplatin, followed by esophagectomy. The overall survival was significantly lower in high Nrf and TXNRD1 groups. Conclusions The study findings indicate that HO-1 status in pre-therapeutic biopsy specimens could predict response to NACRT, and TXNRD1 status could predict overall survival of ESCC patients
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