Thioredoxin system protein expression in carcinomas of the pancreas, bile duct and ampulla

Al-hadyan, Khaled; Storr, Sarah; Zaitoun, Abed; Lobo, Dileep; Martin, Stewart

Abstract

Background: Pancreatic cancer (PC), including the ampulla and bile duct, is very aggressive, and thus difficult to treat with effective therapies. The current treatment options have failed to improve PC five-year survival rates over the last 30 to 40 years, which remain very low, at ~3%; there is, therefore, an urgent need to identify new targets and treatment modalities (1). Methods: The protein expression of thioredoxin (Trx), thioredoxin reductase (TrxR) and thioredoxin interacting protein (TxNIP) was assessed in two cancer patient cohorts by standard immunohistochemistry using tissue microarrays. The first cohort was composed of 85 pancreatic adenocarcinomas (PAD) and the second of 145 cancers of the bile duct and ampulla. Results: In the PAD cohort, high cytoplasmic TrxR expression significantly associated with lymph node metastasis (P = 0.033). High expression of cytoplasmic (P = 0.018) and nuclear (P = 0.006) Trx were significantly associated with better overall survival, with nuclear Trx expression remaining significantly associated with survival in multivariate Cox-regression (Hazard Ratio (HR) 0.316; 95% Confidence Interval (95% CI) 0.174-0.573; P < 0.0001) when potentially confounding factors were included (gender, age, tumour size, tumour grade, tumour stage, lymph node status, perineural and venous invasion). In cancers of the bile duct and ampulla, high expression of nuclear TrxR and high cytoplasmic TxNIP were associated with patients aged above 60 years (P = 0.024 and P = 0.049 respectively). Associations were also observed between high nuclear TrxR expression and the presence of venous (P = 0.001) and perineural (P = 0.021) invasion. Low cytoplasmic TxNIP expression was also associated with the presence of perineural invasion (P = 0.025). High expression of cytoplasmic TxNIP was significantly associated with better overall survival (P = 0.0002), which remained significant in multivariate Cox-regression analysis (HR 0.548; 95% CI 0.340-0.882; P = 0.013) when potentially confounding factors were included (tumour grade, stage, lymph node status, perineural and venous invasion). Conclusion: Current findings demonstrate the prognostic importance of Trx system protein expression in pancreatic, bile duct and ampullary cancers, with expression of certain members potentially being involved in disease progression. Current findings warrant a larger follow-up study.

Citation

Al-hadyan, K., Storr, S., Zaitoun, A., Lobo, D., & Martin, S. Thioredoxin system protein expression in carcinomas of the pancreas, bile duct and ampulla

• Working Paper Type: Working Paper
• Deposit Date: Oct 11, 2020
• Publicly Available Date: Feb 9, 2021
• Public URL: https://nottingham-repository.worktribe.com/output/4248634
• Publisher URL: https://www.researchsquare.com/article/rs-3545/v1
• Additional Information: This is a preprint.