TFRC基因扩增诱导鼻咽癌放疗耐受导致肿瘤复发的分子机制

Relapse is one of the main cause of failure after radiotherapy for nasopharyngeal carcinoma, and radioresistance is the primary factor leading to tumor relapse. Thus, idenifying key molecular factor in radio-resistance would be of great value for diagnosis and treatment in nasopharyngeal carcinoma. Recently, using RNA-seq, we found that the expression of transferrin receptor (TFRC) was significantly up-regulated in patients with tumor relapse after radiotherapy. Furthermore, our results showed that TFRC locus was amplified in a large portion. TFRC interacted with DVL1 and upregulated phosphorylatd DVL1, consequently activated and Wnt/β-catenin signaling, which promoted the cancer stem cells traits. Moreover, TFRC acts as a ligand to continuously activate Akt signaling, which enhanced tumor cells anti-apoptosis, leading to radio-resistance. However, the molecular mechanism needs to be elucidated. Therefore, this project aims to integrate molecular biology, cell biology and animal experimental model, employs ionizing radiation and analyzes clinical specimen data, further investigates the mechanisms that TFRC affects the radio-resistance in NPC, which may supply new biomarkers and targets for the diagnosis and treament of NPC, and improve the survival of patients with NPC.

复发是鼻咽癌放疗失败的主要原因之一，而放疗抵抗是导致复发的首要因素，深入探讨放疗抵抗的关键分子机制对提高鼻咽癌患者的生存率具有重要的意义。近期，通过对肿瘤组织样品进行RNA测序，我们发现转铁蛋白受体（TFRC）在放疗后复发的鼻咽癌样品中显著扩增并表达上调；进一步实验结果显示TFRC①通过结合DVL1上调其磷酸化水平，激活Wnt/β-catenin信号通路，维持肿瘤干细胞特性；②作为Akt信号通路的上游受体，持续激活该通路，增强抗凋亡能力而导致放疗耐受。然而以上详细的分子机制有待阐明。本研究拟综合分子生物学、细胞生物学及体内动物模型实验，采用X射线照射处理等特殊方法，并结合临床标本分析，深入探讨TFRC诱导放疗耐受引起肿瘤复发的分子机制，为预测鼻咽癌放疗敏感性提供新的理论依据，寻找新型治疗靶点，以最终提高鼻咽癌患者生存率。

放射抵抗是导致鼻咽癌复发和转移的主要原因。鉴定调控鼻咽癌放射抵抗的关键分子并阐明其作用机制，将为鼻咽癌临床诊治提供新型分子标志物和靶点。围绕该研究主线，本项目取得的主要成果包括：1、TFRC在鼻咽癌中存在基因扩增并高表达，且TFRC表达与放射敏感性及肿瘤预后密切相关，上调TFRC显著增加电离辐射后鼻咽癌细胞内铁含量和ROS水平，并激活细胞内线粒体凋亡途径，促进细胞凋亡，增强肿瘤细胞放射敏感性；CHAF1B在鼻咽癌中高表达，通过激活DNA依赖性蛋白激酶途径促进DNA损伤修复，从而抑制线粒体凋亡途径，导致鼻咽癌细胞放射抵抗（Biomedicine & Pharmacotherapy，2020）。2、近期，我们发现40%-75%的辐照诱导的鼻咽癌细胞死亡是由GSDME介导的细胞焦亡。去泛素酶OTUD4结合GSDME蛋白，通过去泛素化增加其蛋白稳定性，进而促进GSDME依赖的细胞焦亡，最终提高鼻咽癌细胞的放射敏感性（Journal of Experimental & Clinical Cancer Research，2022）。3、一项针对同期放化疗联合卡培他滨辅助化疗的III期前瞻性随机对照临床研究表明，卡培他滨作辅助化疗可将局部晚期鼻咽癌患者的5年FFS从65.9%提高至78.5%，且安全性良好（JAMA Oncology，2022）。这些研究成果揭示了鼻咽癌放射抵抗的新机制，为临床肿瘤诊治提供了潜在的新策略。项目资助发表第一/通讯作者论文6篇。