PO.MCB04.02 · 分子与细胞生物学
活性氧(ROS)敏感的SOX4信号通路介导食管腺癌的铁死亡
Reactive oxygen species (ROS)-sensitive SOX4 signaling mediates ferroptosis in esophageal adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：食管腺癌(EAC)是一种主要由胃食管反流病(GERD)驱动的恶性肿瘤，对化疗仍然高度耐药，导致临床预后不良。铁死亡是一种铁依赖性、非凋亡性的调节性细胞死亡形式，其特征为脂质过氧化和氧化性膜损伤。SOX4是一种关键的转录因子，已被广泛认为与肿瘤发生和癌症干性维持有关。本研究探讨SOX4介导的抗铁死亡作为EAC化疗耐药机制，重点关注活性氧(ROS)敏感的APE1-氧化还原-STAT3-SOX4信号轴，目标是确定新的治疗策略。
方法：采用了公共数据集和多种实验模型，包括3D器官型培养、患者来源类器官和肿瘤球。使用患者来源异种移植(PDX)模型进行体内验证。
结果：对EAC公共数据集的分析显示SOX4转录特征在肿瘤组织中显著富集。在模拟反流条件(酸性胆盐暴露，ABS)下，升高的ROS和APE1蛋白诱导了SOX4激活，而使用ROS清除剂N-乙酰-L-半胱氨酸(NAC)处理则阻断了ABS诱导的SOX4上调。染色质免疫沉淀(ChIP)试验在SOX4启动子内鉴定出一个STAT3结合位点，表明作为APE1氧化还原敏感转录因子的STAT3直接调控SOX4表达。沉默APE1或药理学抑制STAT3在反流条件和奥沙利铂处理下均抑制SOX4表达。单样本基因集富集分析(ssGSEA)显示，在TCGA EAC队列中铁死亡相关信号与SOX4特征之间存在强相关性。值得注意的是，SOX4敲低降低了GPX4表达，并使内在耐药的SK-GT-4细胞和获得性奥沙利铂耐药的FLO-1细胞对奥沙利铂敏感。这些发现在使用APE1氧化还原特异性抑制剂APX2009联合奥沙利铂处理的PDX肿瘤中得到验证。
结论：ROS/APE1依赖的SOX4激活在EAC的抗铁死亡和化疗耐药中发挥关键作用。靶向APE1的氧化还原功能代表了一种有前景的治疗方法，可克服SOX4介导的铁死亡耐药并增强EAC的化疗疗效。
查看英文原文 English abstract
Introduction: Esophageal adenocarcinoma (EAC), a malignancy largely driven by gastroesophageal reflux disease (GERD), remains highly resistant to chemotherapy, resulting in poor clinical outcomes. Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death characterized by lipid peroxidation and oxidative membrane injury. SOX4, a critical transcription factor, has been broadly implicated in tumorigenesis and the maintenance of cancer stemness. This study investigates SOX4-mediated anti-ferroptosis as a mechanism of chemoresistance in EAC, focusing on the reactive oxygen species (ROS)-sensitive APE1-redox-STAT3-SOX4 signaling axis, with the goal of identifying novel therapeutic strategies.
Methods: Public datasets and multiple experimental models were employed, including 3D organotypic cultures, patient-derived organoids, and tumor spheres. In vivo validation was performed using a patient-derived xenograft (PDX) model.
Results: Analysis of EAC public datasets revealed significant enrichment of the SOX4 transcriptional signature in tumor tissues. SOX4 activation was induced by elevated ROS and APE1 protein under reflux-mimicking conditions (acidic bile salt exposure, ABS), while treatment with a ROS scavenger, N-acetyl-l-cysteine (NAC), blocked ABS-induced SOX4 upregulation. Chromatin immunoprecipitation (ChIP) assay identified a STAT3 binding site within the SOX4 promoter, indicating that STAT3, an APE1 redox-sensitive transcription factor, directly regulates SOX4 expression. Silencing of APE1 or pharmacological inhibition of STAT3 suppressed SOX4 expression under both reflux conditions and oxaliplatin treatment. Single-sample gene set enrichment analysis (ssGSEA) demonstrated a strong correlation between ferroptosis-related signaling and the SOX4 signature in the TCGA EAC cohort. Notably, SOX4 knockdown reduced GPX4 expression and sensitized both intrinsically resistant SK-GT-4 cells and acquired oxaliplatin-resistant FLO-1 cells to oxaliplatin. These findings were validated in PDX tumors treated with the APE1 redox-specific inhibitor APX2009 in combination with oxaliplatin.
Conclusion: ROS/APE1-dependent activation of SOX4 plays a crucial role in anti-ferroptosis and chemoresistance in EAC. Targeting the redox function of APE1 represents a promising therapeutic approach to overcome SOX4-mediated ferroptosis resistance and enhance chemotherapy efficacy in EAC.
利益披露 Disclosure
H. Lu, None.