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Exosomal miR-200b-3p induce macrophage polarization by regulating transcriptional repressor ZEB1 in hepatocellular carcinoma

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A Correction to this article was published on 28 November 2023

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Abstract

Purpose

Accumulating evidence has elucidated that the interaction between cancer cells and M2 macrophages plays an important role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the mechanism connecting tumor-derived exosomes, M2 polarization of macrophages, and liver metastasis remain unclear. Therefore, it is necessary to explore their influence on the tumor microenvironment of HCC.

Methods

Transmission electron microscopy, nanometer particle testing, and special biomarker analysis were utilized to characterize exosomes, while the differential expression of microRNAs was evaluated using high-throughput sequencing technology. The functions of miR-200b-3p exosomes were confirmed using in vitro and in vivo assays. The interactions between microRNAs and ZEB1 as well as cancer cells and macrophages were measured using RNA pull-down and luciferase gene reporter assays.

Results

Using in silico analysis, we identified high levels of miR-200b-3p exosome expression in patients with HCC, particularly with relapsed HCC. We demonstrated that HCC cell-derived miR-200b-3p exosomes were internalized by M0 macrophages and induced M2 polarization by downregulating ZEB1 and upregulating interleukin-4. As a result, the JAK/STAT signaling pathway was activated in M2 macrophages, leading to increased PIM1 and VEGFα expression. These cell factors accelerated the proliferation and metastasis of HCC, resulting in a feedback loop between HCC cells and M2 macrophages.

Conclusion

The study illustrates that HCC cell-derived miR-200b-3p exosomes facilitate the proliferation and polarization of macrophages by modulating cytokine secretion and the JAK/STAT signaling pathway, leading to the metastasis of HCC. These findings demonstrate the existence of a novel feedback loop between cancer cells and immune cells in the tumor microenvironment, presenting a new concept in cancer research.

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Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Availability of data and material

All data are available in a public, open-access repository.

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References

  1. Tran NH. Shifting epidemiology of hepatocellular carcinoma in far Eastern and Southeast Asian patients: explanations and implications. Curr Oncol Rep. 2022;24:187–193

    Article  PubMed  Google Scholar 

  2. Kaymak I, Williams KS, Cantor JR, Jones RG. Immunometabolic Interplay in the Tumor Microenvironment. Cancer Cell. 2021;39:28–37

    Article  CAS  PubMed  Google Scholar 

  3. Ren X, Zhang L, Zhang Y, Li Z, Siemers N, Zhang Z. Insights gained from single-cell analysis of immune cells in the tumor microenvironment. Annu Rev Immunol. 2021;39:583–609

    Article  CAS  PubMed  Google Scholar 

  4. Ugel S, Cane S, De Sanctis F, Bronte V. Monocytes in the tumor microenvironment. Annu Rev Pathol. 2021;16:93–122

    Article  CAS  PubMed  Google Scholar 

  5. Wong-Rolle A, Wei HK, Zhao C, Jin C. Unexpected guests in the tumor microenvironment: microbiome in cancer. Protein Cell. 2021;12:426–435

    Article  PubMed  Google Scholar 

  6. Padda J, Khalid K, Khedr A, Patel V, Al-Ewaidat OA, et al. Exosome-derived microRNA: efficacy in cancer. Cureus. 2021;13: e17441

    PubMed  PubMed Central  Google Scholar 

  7. Li C, Qin F, Wang W, Ni Y, Gao M, Guo M, Sun G. hnRNPA2B1-mediated extracellular vesicles sorting of miR-122-5p potentially promotes lung cancer progression. Int J Mol Sci. 2021;22(23):12866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fu C, Jiang L, Hao S, Liu Z, Ding S, Zhang W, et al. Activation of the IL-4/STAT6 signaling pathway promotes lung cancer progression by increasing M2 myeloid cells. Front Immunol. 2019;10:2638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin YJ, Goretzki A, Schulke S. Immune metabolism of IL-4-activated B cells and Th2 cells in the context of allergic diseases. Front Immunol. 2021;12: 790658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu Q, Zhou L, Lv D, Zhu X, Tang H. Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression. J Hematol Oncol. 2019;12:53

    Article  PubMed  PubMed Central  Google Scholar 

  11. Liang Y, Duan L, Lu J, Xia J. Engineering exosomes for targeted drug delivery. Theranostics. 2021;11:3183–3195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kugeratski FG, Kalluri R. Exosomes as mediators of immune regulation and immunotherapy in cancer. FEBS J. 2021;288:10–35

    Article  PubMed  Google Scholar 

  13. Matsubara K, Matsubara Y, Uchikura Y, Sugiyama T. Pathophysiology of preeclampsia: the role of exosomes. Int J Mol Sci. 2021;22(5):2572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li C, Zhou T, Chen J, Li R, Chen H, Luo S, et al. The role of exosomal miRNAs in cancer. J Transl Med. 2022;20:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huang X, Li Y, Fu M, Xin HB. Polarizing macrophages in vitro. Methods Mol Biol. 2018;1784:119–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pan J, Zang Y. LINC00667 Promotes progression of esophageal cancer cells by regulating miR-200b-3p/SLC2A3 axis. Dig Dis Sci. 2022;67(7):2936–47.

    Article  CAS  PubMed  Google Scholar 

  17. Ma X, Ying Y, Sun J, Xie H, Li J, He L, et al. circKDM4C enhances bladder cancer invasion and metastasis through miR-200bc-3p/ZEB1 axis. Cell Death Discov. 2021;7:365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu L, Jiang H, Pan H, Zhu X. LncRNA XIST promotes liver cancer progression by acting as a molecular sponge of miR-200b-3p to regulate ZEB1/2 expression. J Int Med Res. 2021;49:3000605211016211

    CAS  PubMed  Google Scholar 

  19. Guo Y, Lu X, Chen Y, Rendon B, Mitchell RA, Cuatrecasas M, Cortés M, Postigo A, Liu Y, Dean DC. Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells. Sci Adv. 2021;7(21):eabd7455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Qian Y, Arellano G, Ifergan I, Lin J, Snowden C, Kim T, et al. ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis. Cell Rep. 2021;36: 109602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Plaschka M, Benboubker V, Grimont M, Berthet J, Tonon L, Lopez J, Le-Bouar M, Balme B, Tondeur G, de la Fouchardière A, Larue L, Puisieux A, Grinberg-Bleyer Y, Bendriss-Vermare N, Dubois B, Caux C, Dalle S, Caramel J. ZEB1 transcription factor promotes immune escape in melanoma. J Immunother Cancer. 2022;10(3):e003484

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu M, Zhang Y, Yang J, Cui X, Zhou Z, Zhan H. ZIP4 increases expression of transcription factor ZEB1 to promote integrin alpha3beta1 signaling and inhibit expression of the gemcitabine transporter ENT1 in pancreatic cancer cells. Gastroenterology. 2020;158:679-692 e671

    Article  CAS  PubMed  Google Scholar 

  23. Feldker N, Ferrazzi F, Schuhwerk H, Widholz SA, Guenther K. Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer. EMBO J. 2020;39: e103209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13:156

    Article  PubMed  PubMed Central  Google Scholar 

  25. Xun J, Du L, Gao R, Shen L, Wang D, Kang L. Cancer-derived exosomal miR-138-5p modulates polarization of tumor-associated macrophages through inhibition of KDM6B. Theranostics. 2021;11:6847–6859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mirlekar B. Tumor promoting roles of IL-10, TGF-beta, IL-4, and IL-35: its implications in cancer immunotherapy. SAGE Open Med. 2022;10:20503121211069012

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen PH, Anderson L, Zhang K, Weiss GA. Eosinophilic gastritis/gastroenteritis. Curr Gastroenterol Rep. 2021;23:13

    Article  PubMed  Google Scholar 

  28. Peng M, Zhang Q, Cheng Y, Fu S, Yang H, Guo X, et al. Apolipoprotein A-I mimetic peptide 4F suppresses tumor-associated macrophages and pancreatic cancer progression. Oncotarget. 2017;8:99693–99706

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tao S, Chen Q, Lin C, Dong H. Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway. J Exp Clin Cancer Res. 2020;39:191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rahal OM, Wolfe AR, Mandal PK, Larson R, Tin S. Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer. Int J Radiat Oncol Biol Phys. 2018;100:1034–1043

    Article  CAS  PubMed  Google Scholar 

  31. Cui J, Shan K, Yang Q, Qi Y, Qu H, Li J, et al. Prostaglandin E3 attenuates macrophage-associated inflammation and prostate tumour growth by modulating polarization. J Cell Mol Med. 2021;25:5586–5601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Not available.

Funding

Medical and health science and Technology Development of Shandong (202104080599); Natural Science Foundation of Shandong Province (ZR2022QH066).

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Authors and Affiliations

  1. Shandong Cancer Hospital and Institute, Shandong Fist Medical University and Shandong Academy of Medical Science, No 440, Jiyan Road, Ji’nan, Shandong, China

    Ying Xu & Zhongchao Li

  2. Jinan Third People’s Hospital, Shandong, China

    Guangchao Luan

  3. The First Affiliated Hospital of Shandong First Medical University, Shandong, China

    Feng Liu

  4. Shandong University of Traditional Chinese Medicine, Shandong, China

    Yuhua Zhang

  5. Shandong Fist Medical University and Shandong Academy of Medical Science, Shandong, China

    Ziming Liu

  6. Binzhou Medical University Hospital, Shandong, China

    Tao Yang

Authors
  1. Ying Xu
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  4. Yuhua Zhang
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Contributions

YX supervised the study, supported the fund, wrote the manuscript, designed experiments, and constructed figures. GL analyzed some partial data and figures and collected clinical samples. Feng Liu disposed of the review of clinicopathological specimens and guaranteed their source of them. ZL contributed to clinical sample collection and savings. ZL was in charge of in vivo experiments, for example, nude mice were fed and cared for, and subcutaneous tumors were measured. YZ installed and disposed of the data from databases and software. TY managed the color blending of the figures and checked the article format.

Corresponding author

Correspondence to Ying Xu.

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Conflict of interest

Ying Xu, Guangchao Luan, Feng Liu, Yuhua Zhang, Zhongchao Li, Ziming Liu and Tao Yang declare that they have no conflicts of interest in this work.

Animal ethics

All animals’ care was in accordance with institution guidelines.

Ethics approval and consent to participate

All procedures involving human participants were performed in accordance with Harbin Medical University’s ethical committee. All patients provided their written informed consent. The study protocol was approved by the institution’s ethics committee research.

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Written informed consent for publication was obtained from all the participants.

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Xu, Y., Luan, G., Liu, F. et al. Exosomal miR-200b-3p induce macrophage polarization by regulating transcriptional repressor ZEB1 in hepatocellular carcinoma. Hepatol Int 17, 889–903 (2023). https://doi.org/10.1007/s12072-023-10507-y

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  • DOI: https://doi.org/10.1007/s12072-023-10507-y

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