NRF2 调控 SLC7A11 抑制食管鳞癌细胞铁死亡进而增强放射敏感性。

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis.

机构信息

Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Academy of Medical Sciences, Jinan, 250117, China.

出版信息

J Transl Med. 2021 Aug 26;19(1):367. doi: 10.1186/s12967-021-03042-7.

DOI:10.1186/s12967-021-03042-7

PMID:34446045

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8393811/

Abstract

BACKGROUND

Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11's expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC.

METHODS

We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps.

RESULTS

NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features.

CONCLUSION

Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

摘要

背景

溶质载体家族 7 成员 11（SLC7A11）是半胱氨酸/谷氨酸转运体的一个组成部分，在肿瘤生长中发挥关键作用；然而，其对食管鳞状细胞癌（ESCC）放射敏感性的潜在影响尚不清楚。本研究旨在阐明 SLC7A11 的表达及其与 ESCC 中核因子红细胞 2（NRF2）相关放射抵抗的核表达之间的关系。

方法

我们纳入了 127 例接受根治性放化疗的 ESCC 患者。采用免疫组织化学染色检测 SLC7A11 和 NRF2 核表达，并评估其与临床病理特征和生存率或治疗反应的关系。采用 Western blot、双报告基因检测和染色质免疫沉淀（ChIP）测序分析其在体外的关系。通过多个验证步骤研究其在放射抵抗中的作用。

结果

NRF2 核表达和 SLC7A11 表达在 ESCC 组织中过度表达，且二者呈正相关。NRF2 核表达与肿瘤长度、淋巴结转移和 TNM 分期显著相关，而 SLC7A11 表达与淋巴结转移相关。高 NRF2 核表达和 SLC7A11 表达的患者总生存期和无进展生存期明显缩短，治疗反应较差。多变量模型显示，NRF2 核表达和 SLC7A11 表达、性别和肿瘤部位是独立的预后因素。体外分析证实，NRF2 过度激活通过直接结合其启动子区域诱导 SLC7A11 表达，促进放射抵抗，降低放疗诱导的脂质过氧化水平、PTGS2 表达和放疗相关的铁死亡形态特征。