Li Siwei, Wang Shuibin, Zhang Lu, Wu Xiaofeng, Tian Longfu, Zou Jiahua, Pi Guoliang
Department of Oncology, Huanggang Central Hospital of Yangtze University, No.126 Qi'an Road, Huanggang City, Hubei Province, 438000, PR China; Hubei Clinical Medical Research Center of Esophageal and Gastric Malignancy, Huanggang City, Hubei Province, 438021, PR China.
Department of Otolaryngology-Head and Neck Surgery, Huanggang Central Hospital of Yangtze University, No.126 Qi'an Road, Huanggang City, Hubei Province, 438000, PR China.
Transl Oncol. 2025 Jan;51:102161. doi: 10.1016/j.tranon.2024.102161. Epub 2024 Nov 5.
Resistance to radiotherapy is a major component in the failure of nasopharyngeal carcinoma (NPC) treatment. Enhancing autophagy in nasopharyngeal carcinoma may increase its radiation sensitivity, making it critical to find autophagy-modulating targets.
The level of KIF15 was determined in NPC patients. Then, radiation-resistant NPC cells were produced to explore the mechanism in NPC. KIF15 was suppressed, and cell function and autophagy-related variables were examined in radiation-resistant NPC cells. Then the autophagy pathway was blocked, and the link between KIF15 and autophagy was confirmed. Finally, an NPC murine model was established, with tumors implanted in aberrant sites, and the relationship discovered at the cell level was confirmed in vivo. All statistical significance was determined using the student's t-test and one-way ANOVA.
Elevated amounts of KIF15 were discovered to be significantly expressed in NPC tissues and played a role in the radioresistance of NPC, a phenomenon attributed to METTL3-mediated m6A methylation. Blocking KIF15 resulted in decreased cell proliferation, increased cell death, and the activation of autophagy, ultimately making NPC more sensitive to radiation. This also resulted in decreased tumor development and increased levels of autophagy and apoptosis in vivo KIF15 interacted with STAT3, retaining it in the cytoplasm. Overexpression of STAT3 reversed the inhibitory effects of KIF15 knockdown on NPC and also reversed the influence of sh-KIF15 on autophagy activation. Inhibition of KIF15 decreased the inhibitory effect of STAT3 on ATG7, thereby upregulating autophagy activation in radio-resistant NPC cells.
The increased expression of KIF15 was found to be associated with the progression of NPC and play a role in the development of radioresistance in NPC. Inhibiting KIF15 was shown to impede tumor growth and improve the sensitivity of NPC to radiotherapy by triggering autophagy via the STAT3/ATG7 pathway.
放疗抵抗是鼻咽癌（NPC）治疗失败的主要因素。增强鼻咽癌中的自噬可能会提高其放射敏感性，因此找到自噬调节靶点至关重要。
测定NPC患者中KIF15的水平。然后制备放射抗性NPC细胞以探究NPC中的机制。抑制KIF15，并检测放射抗性NPC细胞中的细胞功能和自噬相关变量。接着阻断自噬途径，证实KIF15与自噬之间的联系。最后，建立NPC小鼠模型，将肿瘤植入异常部位，并在体内证实细胞水平发现的关系。所有统计学显著性均使用学生t检验和单因素方差分析确定。
发现NPC组织中KIF15表达量升高且在NPC的放射抗性中起作用，这一现象归因于METTL3介导的m6A甲基化。阻断KIF15导致细胞增殖减少、细胞死亡增加以及自噬激活，最终使NPC对放疗更敏感。这也导致体内肿瘤生长减少以及自噬和凋亡水平增加。KIF15与STAT3相互作用，将其保留在细胞质中。STAT3的过表达逆转了KIF15敲低对NPC的抑制作用，也逆转了sh-KIF15对自噬激活的影响。抑制KIF15降低了STAT3对ATG7的抑制作用，从而上调放射抗性NPC细胞中的自噬激活。
发现KIF15表达增加与NPC的进展相关，并在NPC放射抗性的发展中起作用。抑制KIF15可通过STAT3/ATG7途径触发自噬来阻碍肿瘤生长并提高NPC对放疗的敏感性。
