PO.TB06.01 · 肿瘤生物学

FDXR表达是放疗抵抗的直肠癌生物标志物并通过铁死亡赋予抵抗性

FDXR expression is a rectal cancer biomarker of radiation resistance and confers resistance through ferroptosis

编号 7379 展板 16 时间 4/22 09:00–12:00 区域 Section 26 主讲 Sara Soltani Tehrani, MS

分会场 Biological Mechanisms of Tumor and Normal Tissue Response and Clinical Studies

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Sara Soltani Tehrani, May Zin Hlaing, Joseph Fedro, Rami-James Aoun, Karishma Kundu, Sylvain Ferrandon, Matthew F. Kalady

The Ohio State University College of Medicine, Columbus, OH

摘要 Abstract

中文摘要

目的：局部晚期直肠癌的治疗是多模态的，包括全程新辅助治疗（TNT），即放化疗和化疗。对TNT的反应高度可变，并与肿瘤学结局相关。直肠癌放疗反应的生物标志物有限，同时也迫切需要识别可能改善放疗敏感性的潜在治疗靶点。FDXR基因编码一种参与电子传递、铁代谢和铁死亡的线粒体黄素蛋白。本研究评估FDXR在直肠癌放疗反应中的作用。方法：既往对33例直肠癌患者的治疗前活检进行了分析，识别出FDXR在不同AJCC肿瘤消退评分（TRS）之间差异表达。在公共数据集中考察了FDXR表达。通过RT-qPCR在十种结直肠癌（CRC）细胞系中测量FDXR表达，并与放疗敏感性参数（IC50、D10、SF2）相关联。使用慢病毒shRNA构建稳定的FDXR敲低细胞系（HCT116、SW480）。通过Western印迹确认敲低。为评估线粒体形态和结构完整性，采用透射电子显微镜（TEM）。在照射前后评估照射后的克隆形成存活、活力（CCK-8）、脂质过氧化（Image-iT）、线粒体铁（MitoFerroGreen）和ROS水平。结果：在TCGA和GSE87211中，FDXR在直肠肿瘤中较正常组织显著过表达。在我们的患者队列中，较高的FDXR表达与较差的反应（TRS 2-3）相关，并显示出强大的预测能力（AUC=0.8577）。在各CRC细胞系中，FDXR表达与IC50、D10和SF2呈正相关。FDXR敲低导致TEM上线粒体结构完整性丧失，并显著降低克隆形成存活，同时增加放疗诱导的细胞死亡。敲低细胞系表现出更高的线粒体铁、增加的ROS和升高的脂质过氧化。结论：FDXR是直肠癌放疗反应的强效生物标志物。FDXR的缺失通过铁积累、ROS生成和脂质过氧化增强铁死亡，提高放疗敏感性。这些结果提示靶向FDXR可增强放疗疗效，为直肠癌放疗增敏提供了一种新策略。

查看英文原文 English abstract

Purpose: Treatment of locally advanced rectal cancer is multimodal and includes total neoadjuvant therapy (TNT) with chemoradiation and chemotherapy. Response to TNT is highly variable and correlates with oncologic outcomes. There are limited biomarkers for rectal cancer radiation response, and there is also a critical need to identify potential therapeutic targets that could improve radiation sensitivity. The gene FDXR encodes a mitochondrial flavoprotein involved in electron transport, iron metabolism and ferroptosis. This study evaluates the role of FDXR in rectal cancer radiation response. Methods: Pretreatment biopsies from 33 rectal cancer patients were analyzed previously, identifying FDXR as differentially expressed among different AJCC Tumor Regression Score (TRS). FDXR expression was examined in public datasets. FDXR expression was measured by RT-qPCR in ten colorectal cancer (CRC) cell lines and correlated with radiosensitivity parameters (IC50, D10, SF2). Stable FDXR knockdown lines (HCT116, SW480) were generated using lentiviral shRNA. Knockdown was confirmed by Western blot. To assess mitochondrial morphology and structural integrity, Transmission electron microscopy (TEM). Clonogenic survival after irradiation, viability (CCK-8), lipid peroxidation (Image-iT), mitochondrial iron (MitoFerroGreen), and ROS levels were assessed before and after irradiation. Results: FDXR was significantly overexpressed in rectal tumors compared with normal tissue in TCGA and GSE87211. In our patient cohort, higher FDXR expression correlated with poorer response (TRS 2-3) and showed strong predictive ability (AUC=0.8577). Across CRC cell lines, FDXR expression correlated positively with IC50, D10, and SF2. FDXR knockdown caused loss of mitochondrial structural integrity on TEM and significantly reduced clonogenic survival while increasing radiation-induced cell death. Knockdown lines exhibited higher mitochondrial iron, increased ROS, and elevated lipid peroxidation. Conclusions: FDXR is a strong biomarker of rectal cancer radiation response. Loss of FDXR enhances ferroptosis through iron accumulation, ROS generation, and lipid peroxidation, increasing radiosensitivity. These results suggest that targeting FDXR could enhance radiation efficacy, offering a novel strategy for radiosensitization in rectal cancer.

利益披露 Disclosure

S. Soltani Tehrani, None.. M. Zin Hlaing, None.. J. Fedro, None.. R. Aoun, None.. K. Kundu, None.. S. Ferrandon, None.. M. F. Kalady, None.

← 返回 AACR 2026 检索