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MELK previne a morte celular imunogênica induzida por ablação por radiofrequência e a resposta imune antitumoral ao estabilizar FABP5 em malignidades hepatocelulares

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    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

    Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China

Bu-Fu Tang123,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China

Wang-Ting Xu4,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    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

Shi-Ji Fang12,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    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

Jin-Yu Zhu12,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Rong-Fang Qiu125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Lin Shen125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Yang Yang125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Qiao-You Weng125,  
  • Affiliation：

    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

Ya-Jie Wang12,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Jia-Yi Ding125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Xiao-Jie Zhang125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Wei-Qian Chen125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Li-Yun Zheng125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Jing-Jing Song125,  
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

Biao Chen125,  
  • role： Corresponding author通信作者
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

  • Email：zhaozw79@163.com
  • Introduction：* zhaozw79@163.com
Zhong-Wei Zhao125*,  
  • role： Corresponding author通信作者
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

  • Email：minjiangchen@wmu.edu.cn
  • Introduction：minjiangchen@wmu.edu.cn
Min-Jiang Chen125*,  
  • role： Corresponding author通信作者
  • Affiliation：

    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

    Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui 323000, Zhejiang, China

  • Email：jijiansong@zju.edu.cn
  • Introduction：jijiansong@zju.edu.cn
Jian-Song Ji125*

Resumo

Background: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.Methods: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).Results: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.Conclusions: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.

Palavras-chave

Radiofrequency ablation;Liver cancer;Maternal embryonic leucine zipper kinase (MELK);Fatty acid-binding protein 5 (FABP5);Immune microenvironment;Nanoparticles

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