Department of Pathology, Keimyung University Dongsan Hospital, Daegu, Korea.
Department of Immunology, Keimyung University School of Medicine, Daegu, Korea.
J Korean Med Sci. 2023 Jul 3;38(26):e200. doi: 10.3346/jkms.2023.38.e200.
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).
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.
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.
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.
核因子红细胞 2 相关因子 2/kelch 样 ECH 相关蛋白 1（Nrf2/Keap1）信号通路参与调节细胞对氧化应激的反应。Nrf2 作为一种细胞保护因子，可防止炎症、细胞损伤和肿瘤发生，而 Keap1 是 Nrf2 的负调节因子。Nrf2/Keap1 通路的失调导致肿瘤发生和肿瘤细胞的活跃代谢，从而导致对放疗的高度耐药。本研究旨在评估 Nrf2 和 Keap1 在局部晚期直肠癌（LARC）放射敏感性和预后中的预测作用。
共 90 例 LARC 患者在术前放化疗（CRT）后接受手术。在放射治疗前，从肿瘤中获得内镜活检，并通过免疫组织化学评估 Nrf2 和 Keap1 的表达。根据 CRT 后手术的病理肿瘤消退分级评估治疗反应。还记录了无病生存率（DFS）和总生存率。分析了 Nrf2 和 Keap1 免疫反应与临床病理参数之间的关系。
CRT 前核 Nrf2 的过表达与更好的 DFS 显著相关。细胞质 Nrf2 表达与放疗后残留肿瘤更多和更不利的 DFS 相关，表明放射敏感性较低。
LARC 中的 CRT 是一个重要问题，是治疗的一个主要方面。因此，Nrf2/Keap1 的表达可能是术前治疗抵抗的潜在预测因子。相互作用的 Nrf2-Keap1 调节剂也可能有效地适用于 LARC 中的 CRT 效果。
