MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies
Abstract 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 iden...
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BMC
2025-01-01
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| Series: | Military Medical Research |
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| Online Access: | https://doi.org/10.1186/s40779-024-00588-7 |
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| author | Bu-Fu Tang Wang-Ting Xu Shi-Ji Fang Jin-Yu Zhu Rong-Fang Qiu Lin Shen Yang Yang Qiao-You Weng Ya-Jie Wang Jia-Yi Ding Xiao-Jie Zhang Wei-Qian Chen Li-Yun Zheng Jing-Jing Song Biao Chen Zhong-Wei Zhao Min-Jiang Chen Jian-Song Ji |
| author_facet | Bu-Fu Tang Wang-Ting Xu Shi-Ji Fang Jin-Yu Zhu Rong-Fang Qiu Lin Shen Yang Yang Qiao-You Weng Ya-Jie Wang Jia-Yi Ding Xiao-Jie Zhang Wei-Qian Chen Li-Yun Zheng Jing-Jing Song Biao Chen Zhong-Wei Zhao Min-Jiang Chen Jian-Song Ji |
| author_sort | Bu-Fu Tang |
| collection | DOAJ |
| description | Abstract 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. Conclusion 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. |
| format | Article |
| id | doaj-art-ad8aed44703d417daf2bf5335bea4272 |
| institution | Kabale University |
| issn | 2054-9369 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj-art-ad8aed44703d417daf2bf5335bea42722025-02-02T12:13:47ZengBMCMilitary Medical Research2054-93692025-01-0112111810.1186/s40779-024-00588-7MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignanciesBu-Fu Tang0Wang-Ting Xu1Shi-Ji Fang2Jin-Yu Zhu3Rong-Fang Qiu4Lin Shen5Yang Yang6Qiao-You Weng7Ya-Jie Wang8Jia-Yi Ding9Xiao-Jie Zhang10Wei-Qian Chen11Li-Yun Zheng12Jing-Jing Song13Biao Chen14Zhong-Wei Zhao15Min-Jiang Chen16Jian-Song Ji17Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityKey Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, the Fifth Affiliated Hospital of Wenzhou Medical UniversityAbstract 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. Conclusion 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.https://doi.org/10.1186/s40779-024-00588-7Radiofrequency ablationLiver cancerMaternal embryonic leucine zipper kinase (MELK)Fatty acid-binding protein 5 (FABP5)Immune microenvironmentNanoparticles |
| spellingShingle | Bu-Fu Tang Wang-Ting Xu Shi-Ji Fang Jin-Yu Zhu Rong-Fang Qiu Lin Shen Yang Yang Qiao-You Weng Ya-Jie Wang Jia-Yi Ding Xiao-Jie Zhang Wei-Qian Chen Li-Yun Zheng Jing-Jing Song Biao Chen Zhong-Wei Zhao Min-Jiang Chen Jian-Song Ji MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies Military Medical Research Radiofrequency ablation Liver cancer Maternal embryonic leucine zipper kinase (MELK) Fatty acid-binding protein 5 (FABP5) Immune microenvironment Nanoparticles |
| title | MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies |
| title_full | MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies |
| title_fullStr | MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies |
| title_full_unstemmed | MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies |
| title_short | MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies |
| title_sort | melk prevents radiofrequency ablation induced immunogenic cell death and antitumor immune response by stabilizing fabp5 in hepatocellular malignancies |
| topic | Radiofrequency ablation Liver cancer Maternal embryonic leucine zipper kinase (MELK) Fatty acid-binding protein 5 (FABP5) Immune microenvironment Nanoparticles |
| url | https://doi.org/10.1186/s40779-024-00588-7 |
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