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AbstractPurposeOxidative stress has impacts on the KRas and Nrf2/Keap1 pathways, which have multiple interactions with each other and play important roles in colorectal cancer (CRC). This study investigated the expressions of proteins in the KRas and Nrf2/Keap1 pathways and their associations with clinicopathological features in CRC.MethodsThe protein levels of Nrf2, Keap1, Bach1, p62, HO1, KRas, Erk, Raf1 and PI3K in both the tumour and normal tissues of 60 CRC subjects were determined by Western blot and their T/N (tumour/normal tissue) ratios were correlated with clinicopathological features.ResultsThe T/N ratios of proteins in the KRas and Nrf2/Keap1 pathways had correlation patterns and proximity profiles in cluster dendrograms different in CRC with different status of lymphovascular invasion (LVI) or lymph node/distant metastases. The Keap1 protein T/N ratio was a significant predictor (odd ratio: 2.24; 95% confidence interval: 1.26 − 4.38) of LVI, which in turn predicted metastases (11.0; 3.49 − 39.8).ConclusionThe interactions between the KRas and Nrf2/Keap1 pathways may be affected differently by LVI and metastases, and the protein T/N ratio of Keap1 may be helpful for predicting LVI in CRC.

AbstractIntroductionThe Nrf2 (nuclear factor erythroid 2-like 2; NFE2L2)/Keap1 (Kelch-like ECH-associated protein 1) pathway and the TXN (thioredoxin)/GSH (glutathione) system interact mutually and regulate cellular redox with impacts on cancer metastasis and S-glutathionylation of protein, which is an indicator of cell distress. This study investigates the levels of proteins in the Nrf2/Keap1 pathway and the TXN/GSH system and SGP (S-glutathionylated protein) in CRC (colorectal cancer) with or without metastasis.Materials and methodsThe protein levels of Nrf2, Keap1, Bach1 (BTB domain and CNC homolog 1), TXN, TXNRD1 (thioredoxin reductase 1), GSR (glutathione reductase) and SGP with molecular weight 31–172 kDa in the normal and tumour tissues of 64 CRC subjects were determined by Western blot.ResultsThe protein levels and their T/N (tumour/normal tissue) ratios of the Nrf2/Keap1 pathway, the TXN/GSH system and SGP were correlated to different extents in the tissues of CRC subjects with or without lymph node/distant metastasis. The T/N ratios of SGP (odd ratio: 0.19; 95% CI: 0.04–0.74) and lympho-vascular invasion (4.2; 1.39–13.73) were significant predictors for metastasis.ConclusionsSGPs have protein levels correlated with those of the Nrf2/Keap1 pathway and their T/N ratios are a negative predictor for metastasis in CRC.

Background: The Glasgow Prognostic Score and circulating cytokine levels are related to the prognosis of colorectal cancer and the severity of chronic inflammation. The association between the Glasgow Prognostic Score and circulating cytokines in colorectal cancer remains unclear.Methods: The levels of 10 circulating cytokines (TNF-α, TGF-β, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-12, IL-13, and IL-23) were measured in 128 patients with colorectal cancer. The relationship between the Glasgow Prognostic Score, clinicopathologic variables, and cytokine levels was assessed by univariate and multivariate logistic regression analyses. The correlation among cytokines was also examined.Results: Patients with advanced stage colorectal cancer had lower levels of albumin (P= 0.003), higher levels of C-reactive protein (CRP; P< 0.001), carcinoembryonic antigen (CEA; P< 0.001), interferon (IFN)-γ (P< 0.001), and interleukin (IL)-10 (P= 0.006), and shorter survival outcomes (P< 0.001). Patients with a high Glasgow Prognostic Score (1 or 2) had lower 5-year progression-free survival and poor overall survival (log-rank P< 0.001). A high Glasgow Prognostic Score was significantly correlated with abnormal CEA levels (CEA > 5 ng/mL, P= 0.033), and higher levels of tumor necrosis factor (TNF)-α (TNF-α ⩾ 53.9 pg/mL, P= 0.035) and IL-10 (IL-10 ⩾ 75.95 pg/mL, P= 0.008). TNF-α, IFN-γ, IL-1β, IL-4, IL-6, IL-10, IL-13, and IL-23 were significantly correlated with each other (all P< 0.05). Only IL-10 was correlated with abnormal CEA levels (P< 0.001).Conclusion: The Glasgow Prognostic Score and level of circulating cytokines have an intergroup correlation, and there is a close association among cytokines in colorectal cancer.

Oxidative stress is a contributing factor in the carcinogenesis of colorectal cancer. The Nrf2 nuclear factor (erythroid-derived 2)-like 2; NFE2L2 pathway is one of the major cellular defense mechanisms against oxidative stress. This study investigated the expression of the Nrf2 pathway in colorectal cancer. Formalin-fixed paraffin-embedded tissue arrays consisting of the tumor, adjacent normal, and distant normal tissues from the resected specimens of 83 colorectal cancer patients were subjected to immunohistochemical (IHC) staining with antibodies against Nrf2, kelch-like ECH-associated protein 1 (Keap1), p21, P62, Parkinson protein 7 (Park7), prohibitin, BTB and CNC homology 1 (Bach1), CD34 and 8-hydroxy-2′-deoxyguanosine (8-OHdG). The mean IHC density of each IHC staining was digitally analyzed. The results showed that molecules of the Nrf2 pathway were actively expressed, with different expression profiles among the tumor and normal tissues. The oxidative stress, represented by the mean IHC staining density of 8-OHdG, did not differ but was correlated with the expressions of different Nrf2 pathway molecules to a varied extent in tumor and normal tissues of colorectal cancer. Keap1 estimate, 0.49; 95 confidence interval (CI), 0.19-0.79 and Bach1 (estimate, 0.24; 95 CI, 0.11-0.38) were significant predictors for the expression of 8-OHdG and had the closest proximity to Nrf2 in the cluster dendrogram of the tumor and distant normal tissues, respectively. Advanced stage (estimate, 14.9; 95 CI, 2.99-26.8) and current smoker (estimate, 15.6; 95 CI, 1.92-29.3) were significant predictors with high estimates for Bach1 in the adjacent and distant normal tissues, respectively. In colorectal cancer, the molecules of the Nrf2 pathway have different expression profiles and a difference in their importance, especially Keap1 and Bach1, related to Nrf2 and oxidative stress among tumor and normal tissues.