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Updated: Feb 10, 2026
Orthotopic Mouse Model of Colorectal Cancer
Published on: December 4, 2007
Nrf2/P-glycoprotein axis is associated with clinicopathological characteristics in colorectal cancer
Mohammad Reza Sadeghi1, Farhad Jeddi2, Narges Soozangar2
1Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract:
Colorectal cancer (CRC) is the fourth leading cause of cancer-related death worldwide. Activation of ABCB1 gene and its main product, P-glycoprotein, is the common reason for chemoresistance. The nuclear factor-erythroid 2-related factor2 (Nrf2) is directly regulated by Kelch like ECH-associated protein1 (Keap1). In addition, Nrf2 is a key transcriptional factor that regulates efflux transporters, including P-gp. The aim of this study was to investigate the expression levels of Nrf2, Keap1 and ABCB1 in the biopsy samples and their association with clinicopathological features in CRC patients. Both mRNA and protein expression levels were measured by Real-time PCR and immunohistochemistry (IHC), respectively, in biopsies from colonoscopy in 65 CRC patients compared to those in 65 non-CRC individuals. While expression levels of Nrf2 and ABCB1 (P-gp) were markedly higher in both mRNA and protein levels in CRC biopsies (p < 0.01), Keap1 expression level was significantly lower in these samples (p < 0.05). Positive correlations between Nrf2 expression level and tumor size (p = 0.003), lymph node (p = 0.038), distant metastasis (p = 0.008), and smoking status (p = 0.02) were observed. However, P-gp expression was associated only with patient age and smoking status. In addition, there was a positive correlation between protein levels of Nrf2 and P-gp, in both CRC (r = 0.617, p < 0.001) and non-CRC tissues (r = 0.930, p < 0.001). In conclusion, over-expression of Nrf2 and ABCB1/P-gp, as well as down-regulation of mRNA expression level of Keap1 in CRC patients denotes the role of Keap1/Nrf2/ABCB1 axis in CRC progression and chemoresistance. Our data suggest that therapeutic inhibition of Nrf2/ABCB1 signaling can be considered as a novel strategy to improve the efficacy of chemotherapeutics against CRC.
Insights
Colorectal cancer (CRC) shows increased Nrf2 and ABCB1 (P-glycoprotein) expression, linked to chemoresistance. Downregulation of Keap1 suggests the Keap1/Nrf2/ABCB1 pathway
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) is a significant global health concern, ranking as the fourth leading cause of cancer-related mortality worldwide.
- Chemoresistance, often driven by the ABCB1 gene and its product P-glycoprotein (P-gp), poses a major challenge in CRC treatment.
- The Keap1-Nrf2 pathway is a critical regulator of cellular defense mechanisms and drug efflux transporters like P-gp.
Purpose of the Study:
- To investigate the expression levels of Nrf2, Keap1, and ABCB1 in colorectal cancer (CRC) biopsies.
- To determine the association between the expression of these molecules and clinicopathological features in CRC patients.
- To elucidate the role of the Keap1/Nrf2/ABCB1 axis in CRC progression and chemoresistance.
Main Methods:
- Real-time PCR was used to measure mRNA expression levels of Nrf2, Keap1, and ABCB1.
- Immunohistochemistry (IHC) was employed to assess protein expression levels of Nrf2, Keap1, and P-gp.
- Expression levels were analyzed in biopsy samples from 65 CRC patients and 65 non-CRC individuals, with correlations to clinicopathological data.
Main Results:
- CRC biopsies exhibited significantly higher mRNA and protein expression of Nrf2 and ABCB1 (P-gp) compared to non-CRC tissues (p < 0.01).
- Keap1 mRNA expression was significantly lower in CRC biopsies (p < 0.05).
- Nrf2 expression positively correlated with tumor size, lymph node involvement, distant metastasis, and smoking status. P-gp expression correlated with age and smoking status. A strong positive correlation was observed between Nrf2 and P-gp protein levels in both CRC and non-CRC tissues.
Conclusions:
- The observed overexpression of Nrf2 and ABCB1/P-gp, alongside the downregulation of Keap1 in CRC, highlights the involvement of the Keap1/Nrf2/ABCB1 axis in CRC pathogenesis and chemoresistance.
- These findings suggest that targeting the Nrf2/ABCB1 signaling pathway could represent a novel therapeutic strategy to enhance the effectiveness of chemotherapy in CRC treatment.
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