Tang Bu-Fu, Xu Wang-Ting, Fang Shi-Ji, Zhu Jin-Yu, Qiu Rong-Fang, Shen Lin, Yang Yang, Weng Qiao-You, Wang Ya-Jie, Ding Jia-Yi, Zhang Xiao-Jie, Chen Wei-Qian, Zheng Li-Yun, Song Jing-Jing, Chen Biao, Zhao Zhong-Wei, Chen Min-Jiang, Ji Jian-Song
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Mil Med Res. 2025 Jan 27;12(1):5. doi: 10.1186/s40779-024-00588-7.
Radiofrequency ablation (RFA) is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality. Understanding the biological process related with RFA treatment is important for improving treatment strategy. This study aimed to identify the critical targets for regulating the efficacy of RFA.
The RFA treatment in hepatocellular carcinoma (HCC) tumor models in vivo, was analyzed by RNA sequencing technology. The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells. Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase (MELK).
It was found that RFA treatment upregulated MELK expression, and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response, including anti-tumoral macrophage polarization and increased CD8 T cell cytotoxicity in HCC. Mechanically, MELK binds to fatty acid-binding protein 5 (FABP5), and affects its ubiquitination through the K48R pathway to increase its stability, thereby activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling axis to weaken the RFA-mediated antitumor effect. In addition, the synthesis of arginylglycylaspartic acid (RGD)-lipid nanoparticles (LNPs) targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC.
MELK is a therapeutic target by regulating RFA efficacy in HCC, and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer.
射频消融（RFA）是一种对肝癌具有无限潜力的有效治疗方法，可有效降低患者死亡率。了解与RFA治疗相关的生物学过程对于改进治疗策略至关重要。本研究旨在确定调节RFA疗效的关键靶点。
采用RNA测序技术分析体内肝细胞癌（HCC）肿瘤模型中的RFA治疗。还构建了体外对HCC肿瘤细胞的热处理，以探索肿瘤细胞RFA治疗后的机制。应用对肿瘤细胞具有高亲和力的纳米颗粒作为一种新的治疗方法来干扰母源胚胎亮氨酸拉链激酶（MELK）的表达。
发现RFA治疗上调了MELK的表达，抑制MELK可通过免疫原性细胞死亡和抗肿瘤反应促进RFA疗效，包括抗肿瘤巨噬细胞极化和增强HCC中CD8 T细胞的细胞毒性。机制上，MELK与脂肪酸结合蛋白5（FABP5）结合，并通过K48R途径影响其泛素化以增加其稳定性，从而激活蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）信号轴，削弱RFA介导的抗肿瘤作用。此外，靶向肿瘤细胞内在MELK的精氨酰甘氨酰天冬氨酸（RGD）-脂质纳米颗粒（LNP）的合成增强了HCC中RFA的疗效。
MELK是通过调节HCC中RFA疗效的治疗靶点，通过RGD-LNP靶向MELK为提高HCC临床治疗中RFA疗效和对抗肝癌的恶性进展提供了新的见解。
