이전|다음

MELK는 간세포 악성 종양에서 FABP5를 안정화하여 고주파 열절제에 의해 유도된 면역원성 세포 사멸 및 항종양 면역 반응을 방지합니다

  • 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*

추상적인

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.

키워드

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

References

  1. 1..
    Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525-43.
  2. 2..
    Lee TKW, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma—from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19(1):26-44.
  3. 3..
    Xu XL, Liu XD, Liang M, Luo BM. Radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma: systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Radiology. 2018;287(2):461-72.
  4. 4..
    Caraballo Galva LD, Cai L, Shao Y, He Y. Engineering T cells for immunotherapy of primary human hepatocellular carcinoma. J Genet Genomics. 2020;47(1):1-15.
  5. 5..
    Nault JC, Sutter O, Nahon P, Ganne-Carrié N, Séror O. Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations. J Hepatol. 2018;68(4):783-97.
  6. 6..
    Faraoni EY, O’Brien BJ, Strickland LN, Osborn BK, Mota V, Chaney J, et al. Radiofrequency ablation remodels the tumor microenvironment and promotes neutrophil-mediated abscopal immunomodulation in pancreatic cancer. Cancer Immunol Res. 2023;11(1):4-12.
  7. 7..
    Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer. 2020;8(1):e000337.
  8. 8..
    Ma GL, Lin WF. Immune checkpoint inhibition mediated with liposomal nanomedicine for cancer therapy. Mil Med Res. 2023;10(1):20.
  9. 9..
    Zhang S, Huang Y, Pi S, Chen H, Ye F, Wu C, et al. Autophagy-amplifying nanoparticles evoke immunogenic cell death combined with anti-PD-1/PD-L1 for residual tumors immunotherapy after RFA. J Nanobiotechnology. 2023;21(1):360.
  10. 10..
    Yang Z, Zhu Y, Dong Z, Li W, Yang N, Wang X, et al. Tumor-killing nanoreactors fueled by tumor debris can enhance radiofrequency ablation therapy and boost antitumor immune responses. Nat Commun. 2021;12(1):4299.
  11. 11..
    Xia H, Kong SN, Chen J, Shi M, Sekar K, Seshachalam VP, et al. MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence. Cancer Lett. 2016;383(1):85-93.
  12. 12..
    Tang B, Zhu J, Shi Y, Wang Y, Zhang X, Chen B, et al. Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy. Mol Cancer. 2024;23(1):137.
  13. 13..
    Tang B, Zhu J, Liu F, Ding J, Wang Y, Fang S, et al. xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade. Cell Death Dis. 2022;13(4):373.
  14. 14..
    Pitner MK, Taliaferro JM, Dalby KN, Bartholomeusz C. MELK: a potential novel therapeutic target for TNBC and other aggressive malignancies. Expert Opin Ther Targets. 2017;21(9):849-59.
  15. 15..
    Tang B, Wang Y, Xu W, Zhu J, Weng Q, Chen W, et al. Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer. Cancer Lett. 2023;554:216021.
  16. 16..
    Tang B, Zhu J, Fang S, Wang Y, Vinothkumar R, Li M, et al. Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis. Free Radic Biol Med. 2021;172:312-29.
  17. 17..
    Tang BF, Yan RC, Wang SW, Zeng ZC, Du SS. Maternal embryonic leucine zipper kinase in tumor cells and tumor microenvironment: an emerging player and promising therapeutic opportunity. Cancer Lett. 2023;560:216126.
  18. 18..
    Hou Y, Wei D, Zhang Z, Guo H, Li S, Zhang J, et al. FABP5 controls macrophage alternative activation and allergic asthma by selectively programming long-chain unsaturated fatty acid metabolism. Cell Rep. 2022;41(7):111668.
  19. 19..
    Liu RZ, Graham K, Glubrecht DD, Germain DR, Mackey JR, Godbout R. Association of FABP5 expression with poor survival in triple-negative breast cancer: implication for retinoic acid therapy. Am J Pathol. 2011;178(3):997-1008.
  20. 20..
    Kawaguchi K, Senga S, Kubota C, Kawamura Y, Ke Y, Fujii H. High expression of fatty acid-binding protein 5 promotes cell growth and metastatic potential of colorectal cancer cells. FEBS Open Bio. 2016;6(3):190-9.
  21. 21..
    Liu F, Liu W, Zhou S, Yang C, Tian M, Jia G, et al. Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma. J Immunother Cancer. 2020;8(2):e000501.
  22. 22..
    Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for treg suppressive function. Cell Metab. 2020;31(2):422-37.e5.
  23. 23..
    Zhang J, He G, Jin X, Alenezi BT, Naeem AA, Abdulsamad SA, et al. Molecular mechanisms on how FABP5 inhibitors promote apoptosis-induction sensitivity of prostate cancer cells. Cell Biol Int. 2023;47(5):929-42.
  24. 24..
    Ye M, Hu C, Chen T, Yu P, Chen J, Lu F, et al. FABP5 suppresses colorectal cancer progression via mTOR-mediated autophagy by decreasing FASN expression. Int J Biol Sci. 2023;19(10):3115-27.
  25. 25..
    Wang T, Zhang D, Sun D, Gu J. Current status of in vivo bioanalysis of nano drug delivery systems. J Pharm Anal. 2020;10(3):221-32.
  26. 26..
    Du SS, Chen GW, Yang P, Chen YX, Hu Y, Zhao QQ, et al. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation. Int J Radiat Oncol Biol Phys. 2022;112(5):1243-55.
  27. 27..
    Dogan S, Vasudevaraja V, Xu B, Serrano J, Ptashkin RN, Jung HJ, et al. DNA methylation-based classification of sinonasal undifferentiated carcinoma. Mod Pathol. 2019;32(10):1447-59.
  28. 28..
    Zeng X, Liao G, Li S, Liu H, Zhao X, Li S, et al. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatology. 2023;77(4):1122-38.
  29. 29..
    Li M, Hao B, Zhang M, Reiter RJ, Lin S, Zheng T, et al. Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development. Signal Transduct Target Ther. 2021;6(1):330.
  30. 30..
    Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015;25(1):11-7.
  31. 31..
    Chen J, Alduais Y, Zhang K, Zhu X, Chen B. CCAT1/FABP5 promotes tumour progression through mediating fatty acid metabolism and stabilizing PI3K/AKT/mTOR signalling in lung adenocarcinoma. J Cell Mol Med. 2021;25(19):9199-213.
  32. 32..
    Hsiao YH, Chen NC, Koh YC, Nagabhushanam K, Ho CT, Pan MH. Pterostilbene inhibits adipocyte conditioned-medium-induced colorectal cancer cell migration through targeting FABP5-related signaling pathway. J Agric Food Chem. 2019;67(37):10321-9.
  33. 33..
    Liu Z, Dong X, Yi HW, Yang J, Gong Z, Wang Y, et al. Structural basis for the recognition of K48-linked Ub chain by proteasomal receptor Rpn13. Cell Discov. 2019;5:19.
  34. 34..
    Izzo F, Granata V, Grassi R, Fusco R, Palaia R, Delrio P, et al. Radiofrequency ablation and microwave ablation in liver tumors: an update. Oncologist. 2019;24(10):e990-1005.
  35. 35..
    Leone P, Solimando AG, Fasano R, Argentiero A, Malerba E, Buonavoglia A, et al. The Evolving role of immune checkpoint inhibitors in hepatocellular carcinoma treatment. Vaccines (Basel). 2021;9(5):532.
  36. 36..
    Yang H, Zhou H, Wang G, Tian L, Li H, Zhang Y, et al. MELK is a prognostic biomarker and correlated with immune infiltration in glioma. Front Neurol. 2022;13:977180.
  37. 37..
    Liu BH, Xu CZ, Liu Y, Lu ZL, Fu TL, Li GR, et al. Mitochondrial quality control in human health and disease. Mil Med Res. 2024;11(1):32.
  38. 38..
    Sockolosky JT, Dougan M, Ingram JR, Ho CC, Kauke MJ, Almo SC, et al. Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A. 2016;113(19):E2646-54.
  39. 39..
    Furuhashi M, Fucho R, Görgün CZ, Tuncman G, Cao H, Hotamisligil GS. Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest. 2008;118(7):2640-50.
  40. 40..
    Yang X, Deng B, Zhao W, Guo Y, Wan Y, Wu Z, et al. FABP5+ lipid-loaded macrophages process tumour-derived unsaturated fatty acid signal to suppress T-cell antitumour immunity. J Hepatol. 2024. .
  41. 41..
    Li Y, Yang W, Zheng Y, Dai W, Ji J, Wu L, et al. Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis. J Exp Clin Cancer Res. 2023;42(1):6.
  42. 42..
    Seo J, Jeong DW, Park JW, Lee KW, Fukuda J, Chun YS. Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Commun Biol. 2020;3(1):638.

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