Articles
Vol. 69 No. 2 (2025)
Cancer cell-derived exosomal miR-34a inhibits the malignant progression of pancreatic adenocarcinoma cells by restraining the M2 polarization of macrophages
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 24 December 2024
Accepted: 2 April 2025
Accepted: 2 April 2025
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This study aimed to investigate the crosstalk mechanism between pancreatic cancer (PAC) cells and M2 tumor-associated macrophages induced by tumor-derived exosomal miR-34a. MicroRNA and mRNA expression levels were detected using RT-qPCR. Cell Counting Kit-8, wound-healing, transwell assays and flow cytometry were respectively employed to assess cell proliferation, migration, invasion and apoptosis. Enzyme-linked immunosorbent assay was utilized to determine cytokine secretion. Transmission electron microscopy and nanoparticle tracking analyses were performed to detect the exosome morphology and particle size. Phagocytosis of exosomes by macrophages was verified by PKH26 labeling. The effects of exosome-treated macrophages on the epithelial-mesenchymal transition, invasion, and migration of PANC-1 cells were investigated using coculture experiments. The identification of miR-34a's potential targets were determined with TargetScan and validated by a dual-luciferase reporter assay. miR-34a was expressed at low levels in PAC tissues, cells, and exosomes. The overexpression of miR-34a restrains the malignant progression of PANC-1 cells. After miR-34a-overexpressed PANC-1-derived exosomes were phagocytosed by macrophages, the process of M2 polarization in macrophages was obstructed, leading to the suppression of epithelial-mesenchymal transition, migration, and invasion of the cocultured PANC-1 cells. Suppressor of cytokine signaling 3 is a direct target of miR-34a. MiR-34a negatively modulates the suppressor of cytokine signaling 3 to prevent the M2 polarization of macrophages by engaging the Janus kinase/signal transducers and activators of the transcription pathway and influencing the malignancy of PAC cells. miR-34a in cancer cell-derived exosomes inhibits the malignant progression of pancreatic cancer cells by restraining M2 polarization of macrophages.
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Citations
1. Wild CP, Weiderpass E, Stewart BW. World cancer report: cancer research for cancer prevention. Lyon, International Agency for Research on Cancer; 2020.
2. Jain T, Dudeja V. The war against pancreatic cancer in 2020 - advances on all fronts. Nat Rev Gastroenterol Hepatol 2021;18:99-100. DOI: https://doi.org/10.1038/s41575-020-00410-4
3. Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of pancreatic cancer: from epidemiology to practice. Clin Gastroenterol Hepatol 2021;19:876-84. DOI: https://doi.org/10.1016/j.cgh.2020.02.054
4. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab 2019;30:36-50. DOI: https://doi.org/10.1016/j.cmet.2019.06.001
5. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res 2019;79:4557-66. DOI: https://doi.org/10.1158/0008-5472.CAN-18-3962
6. Rhee I. Diverse macrophages polarization in tumor microenvironment. Arch Pharm Res 2016;39:1588-96. DOI: https://doi.org/10.1007/s12272-016-0820-y
7. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-55. DOI: https://doi.org/10.1016/S1471-4906(02)02302-5
8. Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer. Trends Immunol 2019;40:310-27. DOI: https://doi.org/10.1016/j.it.2019.02.003
9. El Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347-57. DOI: https://doi.org/10.1038/nrd3978
10. Royo F, Théry C, Falcón-Pérez JM, Nieuwland R, Witwer KW. Methods for separation and characterization of extracellular vesicles: results of a worldwide survey performed by the ISEV rigor and standardization subcommittee. Cells 2020;9:1955. DOI: https://doi.org/10.3390/cells9091955
11. Kok VC, Yu CC. Cancer-derived exosomes: their role in cancer biology and biomarker development. Int J Nanomedicine 2020;15:8019-36. DOI: https://doi.org/10.2147/IJN.S272378
12. Zhang L, Yu D. Exosomes in cancer development, metastasis, and immunity. Biochim Biophys Acta Rev Cancer 2019;1871:455-68. DOI: https://doi.org/10.1016/j.bbcan.2019.04.004
13. Hsu MT, Wang YK, Tseng YJ. Exosomal proteins and lipids as potential biomarkers for lung cancer diagnosis, prognosis, and treatment. Cancers (Basel) 2022;14:732. DOI: https://doi.org/10.3390/cancers14030732
14. Rashid MH, Borin TF, Ara R, Alptekin A, Liu Y, Arbab AS. Generation of novel diagnostic and therapeutic exosomes to detect and deplete protumorigenic m2 macrophages. Adv Ther (Weinh) 2020;3:1900209. DOI: https://doi.org/10.1002/adtp.201900209
15. Xunian Z, Kalluri R. Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci 2020;111:3100-10. DOI: https://doi.org/10.1111/cas.14563
16. Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 2018;9:191. DOI: https://doi.org/10.1038/s41467-017-02583-0
17. Baig MS, Roy A, Rajpoot S, Liu D, Savai R, Banerjee S, et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res 2020;69:435-51. DOI: https://doi.org/10.1007/s00011-020-01318-0
18. Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol 2020;13:156. DOI: https://doi.org/10.1186/s13045-020-00991-2
19. Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kgamma to promote pancreatic cancer metastasis. Cancer Res 2018;78:4586-98. DOI: https://doi.org/10.1158/0008-5472.CAN-17-3841
20. Xie J, Wen JT, Xue XJ, Zhang KP, Wang XZ, Cheng HH. MiR-221 inhibits proliferation of pancreatic cancer cells via down regulation of SOCS3. Eur Rev Med Pharmacol Sci 2018;22:1914-21.
21. Osada-Oka M, Shiota M, Izumi Y, Nishiyama M, Tanaka M, Yamaguchi T, et al. Macrophage-derived exosomes induce inflammatory factors in endothelial cells under hypertensive conditions. Hypertension Res 2017;40:353-60. DOI: https://doi.org/10.1038/hr.2016.163
22. Pritchard A, Tousif S, Wang Y, Hough K, Khan S, Strenkowski J, et al. Lung tumor cell-derived exosomes promote M2 macrophage polarization. Cells 2020;9:1303. DOI: https://doi.org/10.3390/cells9051303
23. Essandoh K, Li Y, Huo J, Fan GV. miRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock 2016;46:122-31. DOI: https://doi.org/10.1097/SHK.0000000000000604
24. Shinohara H, Kuranaga Y, Kumazaki M, Sugito N, Yoshikawa Y, Takai T, et al. Regulated polarization of tumor-associated macrophages by miR-145 via colorectal cancer-derived extracellular vesicles. J Immunol 2017;199:1505-15. DOI: https://doi.org/10.4049/jimmunol.1700167
25. Zhang L, Liao Y, Tang L. MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J Exp Clin Cancer Res 2019;38:53. DOI: https://doi.org/10.1186/s13046-019-1059-5
26. Welponer H, Tsibulak I, Wieser V, Degasper C, Shivalingaiah G, Wenzel S, et al. The miR-34 family and its clinical significance in ovarian cancer. J Cancer 2020;11:1446. DOI: https://doi.org/10.7150/jca.33831
27. Li Y-Y, Tao Y-W, Gao S, Li P, Zheng J-M, Zhang S-E, et al. Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. EBioMedicine 2018;36:209-20. DOI: https://doi.org/10.1016/j.ebiom.2018.09.006
28. Tang Y, Tang Y, Cheng Y-S. miR-34a inhibits pancreatic cancer progression through Snail1-mediated epithelial–mesenchymal transition and the Notch signaling pathway. Sci Rep 2017;7:38232. DOI: https://doi.org/10.1038/srep38232
29. Gao XR, Ge J, Li WY, Zhou WC, Xu L, Geng D-K. miR‐34a carried by adipocyte exosomes inhibits the polarization of M1 macrophages in mouse osteolysis model. J Biomed Mat Res Part A 2021;109:994-1003. DOI: https://doi.org/10.1002/jbm.a.37088
30. Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, Wang y, et al. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest 2019;129:834-49. DOI: https://doi.org/10.1172/JCI123069
31. Zuo L, Tao H, Xu H, Li C, Qiao G, Guo M, Cao S, et al. Exosomes-coated miR-34a displays potent antitumor activity in pancreatic cancer both in vitro and in vivo. Drug Des Devel Ther 2020;14:3495-507. DOI: https://doi.org/10.2147/DDDT.S265423
32. Liu J, Luo R, Wang J, Luan X, Wu D, Chen H, Hou Q, et al. Tumor Cell-derived exosomal miR-770 inhibits M2 macrophage polarization via targeting MAP3K1 to inhibit the invasion of non-small cell lung cancer cells. Front Cell Dev Biol 2021;9:1409. DOI: https://doi.org/10.3389/fcell.2021.679658
33. Liu ZK, Li C, Zhang RY, Wei D, Shang YK, Yong YL, Kong LM, et al. EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling. Mol Cancer 2021;20:79. DOI: https://doi.org/10.1186/s12943-021-01377-9
34. Dai L, Li Z, Tao Y, Liang W, Hu W, Zhou S, Fu X, et al. Emerging roles of suppressor of cytokine signaling 3 in human cancers. Biomed Pharmacother 2021;144:112262. DOI: https://doi.org/10.1016/j.biopha.2021.112262
35. Ji XC, Shi YJ, Zhang Y, Chang MZ, Zhao G. Reducing suppressors of cytokine signaling-3 (SOCS3) Expression promotes M2 macrophage polarization and functional recovery after intracerebral hemorrhage. Front Neurol 2020;11:586905. DOI: https://doi.org/10.3389/fneur.2020.586905
36. Liu W, Long Q, Zhang W, Zeng D, Hu B, Liu S, Chen L. miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis. Aging (Albany NY) 2021;13:19760. DOI: https://doi.org/10.18632/aging.203388
37. Xin P, Xu X, Deng C, Liu S, Wang Y, Zhou X, Ma H, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol 2020;80:106210. DOI: https://doi.org/10.1016/j.intimp.2020.106210
38. Valentino L, Pierre J. JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol 2006;71:713-21. DOI: https://doi.org/10.1016/j.bcp.2005.12.017
39. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A. SOCS, inflammation, and cancer. JAKSTAT 2013;2:e24053. DOI: https://doi.org/10.4161/jkst.24053
40. Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A. Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 2011;31:980-5. DOI: https://doi.org/10.1161/ATVBAHA.110.207464
41. Yin Y, Liu W, Dai Y. SOCS3 and its role in associated diseases. Hum Immunol 2015;76:775-80. DOI: https://doi.org/10.1016/j.humimm.2015.09.037
42. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374:1-20. DOI: https://doi.org/10.1042/bj20030407
43. Hjazi A, Obaid RF, Ali SS, Abdullaev B, Alsaab HO, Huldani H, et al. The cross-talk between LncRNAs and JAK-STAT signaling pathway in cancer. Pathol Res Pract 2023;248:154657. DOI: https://doi.org/10.1016/j.prp.2023.154657
44. Keewan E, Matlawska-Wasowska K. The emerging role of suppressors of cytokine signaling (SOCS) in the development and progression of leukemia. Cancers (Basel) 2021;13:4000. DOI: https://doi.org/10.3390/cancers13164000
45. Himpe E, Kooijman R. Insulin-like growth factor-I receptor signal transduction and the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Biofactors 2009;35:76-81. DOI: https://doi.org/10.1002/biof.20
46. Chikuma S, Kanamori M, Mise-Omata S, Yoshimura A. Suppressors of cytokine signaling: potential immune checkpoint molecules for cancer immunotherapy. Cancer Sci 2017;108:574-80. DOI: https://doi.org/10.1111/cas.13194
Supporting Agencies
Yunnan Science and Technology DepartmentHow to Cite
1.
Long K, Kui X, Zeng Q, Dong W. Cancer cell-derived exosomal miR-34a inhibits the malignant progression of pancreatic adenocarcinoma cells by restraining the M2 polarization of macrophages. Eur J Histochem [Internet]. 2025 Apr. 17 [cited 2025 Dec. 19];69(2). Available from: https://www.ejh.it/ejh/article/view/4176
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