Clinicopathologic significance of CXCR4 and Nrf2 in colorectal cancer

Abstract

The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer (CRC) tissue specimens and investigated their correlation with patient clinicopathologic characteristics. We determined CXCR4 and Nrf2 expression in 76 CRC tissue specimens and paired normal tissue specimens by immunohistochemistry and real-time PCR. We found that the protein and mRNA transcript levels of CXCR4 were significantly higher in CRC tissue specimens than in paired normal tissues, while the expressions of Nrf2 protein and mRNA were increased in CRC tissues compared to distant non-cancerous tissues. High expression level of CXCR4 was positively correlated with poorly differentiated (P = 0.031), more advanced tumor-node-metastasis (TNM) stage (P = 0.019), lymph node metastasis (P = 0.007) and distant metastasis (P = 0.018). However, the expression of Nrf2 protein was positively correlated with larger tumor size (P = 0.049), more advanced TNM stage (P = 0.013), lymph node metastasis (P = 0.016) and distant metastasis (P = 0.023). Moreover, there was a strong relationship between CXCR4 and Nrf2 expression in CRC tissues, indicating that high Nrf2 expression may contribute to CXCR4 overexpression. In addition, combined expression of CXCR4 and Nrf2 strongly correlated with lymph node metastasis and distant metastasis (P = 0.003). Furthermore, we found that combined high expression of CXCR4 and Nrf2 had stronger correlation with lymph node metastasis and distant metastasis than any single molecule did. This study indicated that the abnormal expression of CXCR4 and Nrf2 contributed to the progression of CRC.

Keywords: CXCR4; Nrf2; biomarker; colorectal cancer.

Fig. 1. Immunohistochemistry of CXCR4 and Nrf2 in colorectal (CRC) and paired adjacent non-tumors tissues.

A: Negative expression of CXCR4 in adjacent non-tumors tissues (×200); B: Negative expression of CXCR4 in CRC tissues (×200); C: Positive expression of CXCR4 in CRC tissues (×200); D: Negative expression of Nrf2 in adjacent non-tumors tissues (×200); E: Negative expression of Nrf2 in CRC tissues (×200); F: Positive expression of Nrf2 in CRC tissues (×200).

Fig. 2. CXCR4 and Nrf2 mRNA levels were quantified by real-time PCR in 76 patients.

A: The relative expression of CXCR4 mRNA in CRC compared to paired normal tissues; B: The relative expression of Nrf2 mRNA, which compared to adjacent non-tumors tissues, was quantified by Real-time PCR in 76 CRC tissues. (**P < 0.01).