J Korean Med Sci.  2023 Jul;38(26):e200. 10.3346/jkms.2023.38.e200.

Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis

• Park JM
• Kim S
• Bae SU
• Byun SJ
• Seo I
• Lee HW

• KMID: 2544015
• DOI: http://doi.org/10.3346/jkms.2023.38.e200

Abstract

Background
The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathway is involved in the regulation of cellular responses to oxidative stress. Nrf2 acts as a cell protector from inflammation, cellular damage, and tumorigenesis, whereas Keap1 is a negative regulator of Nrf2. Dysregulation of the Nrf2/ Keap1 pathway results in tumorigenesis and the active metabolism of tumor cells, leading to high resistance to radiotherapy. This study aimed to evaluate the predictive role of Nrf2 and Keap1 in the radiosensitivity and prognosis of locally advanced rectal cancer (LARC).
Methods
In total, 90 patients with LARC underwent surgery after preoperative chemoradiotherapy (CRT). Endoscopic biopsies from the tumors were obtained before radiation, and the Nrf2 and Keap1 expressions were assessed by immunohistochemistry. The response to therapy was evaluated after surgery following CRT according to the pathologic tumor regression grade. The disease-free survival (DFS) and overall survival rates were also documented. The association between the Nrf2 and Keap1 immunoreactivity and the clinicopathological parameters was analyzed.
Results
The overexpression of the nuclear Nrf2 before CRT showed a significant correlation with better DFS. The cytoplasmic Nrf2 expression was associated with more residual tumors after radiotherapy and a more unfavorable DFS, indicating lower radiosensitivity.
Conclusion
CRT is an important issue in LARC and is a major aspect of treatment. Thus, the Nrf2/Keap1 expression may be a potential predictor of preoperative therapeutic resistance. The Nrf2-Keap1 modulators that interact with each other may also be effectively applicable to CRT effect in LARC.

Keyword

Rectal Cancer; Radiation Therapy; Tumor Regression; Nrf2; Keap1

Figure

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  Fig. 1 Flow chart of patient selection.

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  Fig. 2 Interpretation of Nrf2 and Keap1 expressions. (A) No nuclear and cytoplasmic staining (Nrf2, ×200). (B) No nuclear and moderate cytoplasmic staining (Nrf2, ×200). (C) Moderate nuclear and weak cytoplasmic staining (Nrf2, ×200). (D) Strong nuclear and strong cytoplasmic staining (Nrf2, ×200). (E) No staining (Keap1, ×200). (F) Weak staining (Keap1, ×200). (G) Moderate staining (Keap1, ×200). (H) Strong staining (Keap1, ×200).Nrf2 = nuclear factor erythroid 2-related factor 2, Keap1 = Kelch-like ECH-associated protein 1.

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  Fig. 3 Association between Keap1 and Nrf2 stains to survival probability. (A) Relationship between Keap1/Nrf2 expressions and disease-free survival. (B) Relationship between Keap1/Nrf2 expressions and overall survival.Keap1 = Kelch-like ECH-associated protein 1, Nrf2 = nuclear factor erythroid 2-related factor 2.

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