Zhang Gong, Duan Guosheng, Yang Zhengyan, Deng Xubin, Han Luwei, Zhu Meiling, Jia Xiaorong, Li Lei
Department of Radiotherapy of the Fifth Clinical Medical College of Shanxi Medical University, People's Hospital of Shanxi Province, Taiyuan, Shanxi.
Department of Oncology of the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
Ann Med Surg (Lond). 2024 Sep 10;86(10):5793-5801. doi: 10.1097/MS9.0000000000002559. eCollection 2024 Oct.
Radiotherapy is widely regarded as the primary therapeutic modality for nasopharyngeal cancer (NPC). Studies have shown that cancer cells with high resistance to radiation, known as radioresistant cancer cells, may cause residual illness, which in turn might contribute to the occurrence of cancer recurrence and metastasis. It has been shown that cancer stem-like cells (CSCs) exhibit resistance to radiation therapy. In the present study, fractionated doses of radiation-induced epithelial-mesenchymal transition (EMT) and ALDH+ CSCs phenotype of NPC tumor spheroids. Furthermore, it has been shown that cells with elevated ALDH activity have increased resistance to the effects of fractionated irradiation. Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular antioxidant systems. A large body of evidence suggests that Nrf2 plays a significant role in the development of radioresistance in cancer. The authors' research revealed that the application of fractionated irradiation resulted in a decline in Nrf2-dependent reactive oxygen species (ROS) levels, thereby mitigating DNA damage in ALDH+ stem-like NPC cells. In addition, immunofluorescence analysis revealed that subsequent to the process of fractionated irradiation of ALDH+ cells, activated Nrf2 was predominantly localized inside the nucleus. Immunofluorescent analysis also revealed that the presence of the nuclear Nrf2+/NQO1+/ALDH1+ axis might potentially serve as an indicator of poor prognosis and resistance to radiotherapy in patients with NPC. Thus, the authors' findings strongly suggest that the radioresistance of ALDH-positive NPC CSCs to fractionated irradiation is regulated by nuclear Nrf2 accumulation. Nrf2 exerts its effects through the downstream effector NQO1/ALDH1, which depends on ROS attenuation.
放射治疗被广泛认为是鼻咽癌（NPC）的主要治疗方式。研究表明，对辐射具有高抗性的癌细胞，即放射抗性癌细胞，可能导致疾病残留，进而可能促使癌症复发和转移的发生。研究表明，癌症干细胞样细胞（CSCs）对放射治疗具有抗性。在本研究中，分次剂量辐射诱导了鼻咽癌肿瘤球体的上皮-间质转化（EMT）和ALDH+ CSCs表型。此外，研究表明，ALDH活性升高的细胞对分次照射的影响具有更高的抗性。核因子红细胞2相关因子2（Nrf2）在调节细胞抗氧化系统中起关键作用。大量证据表明，Nrf2在癌症放射抗性的发展中起重要作用。作者的研究表明，分次照射的应用导致Nrf2依赖的活性氧（ROS）水平下降，从而减轻了ALDH+鼻咽癌干细胞样细胞中的DNA损伤。此外，免疫荧光分析显示，对ALDH+细胞进行分次照射后，活化的Nrf2主要定位于细胞核内。免疫荧光分析还显示，核Nrf2+/NQO1+/ALDH1+轴的存在可能是鼻咽癌患者预后不良和对放疗抗性的潜在指标。因此，作者的研究结果强烈表明，ALDH阳性鼻咽癌CSCs对分次照射的放射抗性是由核Nrf2积累调节的。Nrf2通过下游效应物NQO1/ALDH1发挥作用，这依赖于ROS的衰减。
