M2 Macrophage-derived Exosomal MiR-193b-3p Promotes Progression and Glutamine Uptake of Pancreatic Cancer by Targeting TRIM62

Overview

Journal Biol Direct

Publisher Biomed Central

Specialty Biology

Date 2023 Jan 11

PMID 36631876

Authors

Ke Zhang

Yu-Jie Li

Lin-Jia Peng

Hui-Feng Gao

Lu-Ming Liu

Hao Chen

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic cancer (PC) is a highly lethal malignancy that requires effective novel therapies. M2 macrophages are abundant in the PC microenvironment and promote cancer progression. Exosomes are emerging mediators of the crosstalk between cancer cells and the microenvironment. This study was conducted to explore the role of M2 macrophage-derived exosomes in PC.

Methods: Exosomes derived from M2 macrophages were extracted. miR-193b-3p and TRIM62 were overexpressed or silenced to examine their function in PC. Luminescence assays were used to investigate the interaction between miR-193b-3p and TRIM62. Cell proliferation was examined by EdU staining. Would healing and transwell assays were applied to evaluate cell migration and invasion. Co-immunoprecipitation was used to assess the interaction between TRIM62 and c-Myc. Gene and protein expressions were analyzed by quantitative RT-PCR and immunoblotting, respectively.

Results: M2 macrophage-derived exosomal miR-193b-3p promoted the proliferation, migration, invasion, and glutamine uptake of SW1990 cells. Mechanism study revealed that TRIM62 is a target of miR-193b-3p. TRIM62 inhibited the proliferation, migration, invasion, and glutamine uptake of SW1990 cells by promoting c-Myc ubiquitination. Our data also suggested that TRIM62 expression negatively correlated with miR-193b-3p and c-Myc expression. High-expression of miR-193b-3p and c-Myc predicts poor prognosis, whereas low-expression of TRIM62 predicts poor prognosis in patients with PC.

Conclusion: M2 macrophage-derived exosomal miR-193b-3p enhances the proliferation, migration, invasion, and glutamine uptake of PC cells by targeting TRIM62, resulting in the decrease of c-Myc ubiquitination. This study not only reveals the mechanism underlying the crosstalk between M2 macrophages and PC cells but also suggests a promising therapeutic target for PC.

Citing Articles

Prospect of extracellular vesicles in tumor immunotherapy.

Xia W, Tan Y, Liu Y, Xie N, Zhu H Front Immunol. 2025; 16:1525052.

PMID: 40078996 PMC: 11897508. DOI: 10.3389/fimmu.2025.1525052.

Upregulation of YY1 in M2 macrophages promotes secretion of exosomes containing hsa-circ-0000326 via super-enhancers to facilitate prostate cancer progression.

Guan H, Tao H, Luo J, Wan L, Hu H, Chen L Mol Cell Biochem. 2025; .

PMID: 39960585 DOI: 10.1007/s11010-025-05222-1.

Exosomal circRNAs: Deciphering the novel drug resistance roles in cancer therapy.

Li X, Liu H, Xing P, Li T, Fang Y, Chen S J Pharm Anal. 2025; 15(2):101067.

PMID: 39957900 PMC: 11830318. DOI: 10.1016/j.jpha.2024.101067.

Macrophage-derived extracellular vesicles as new players in chronic non-communicable diseases.

Lin F, Luo H, Wang J, Li Q, Zha L Front Immunol. 2025; 15:1479330.

PMID: 39896803 PMC: 11782043. DOI: 10.3389/fimmu.2024.1479330.

Identification of M2 macrophage-related genes for establishing a prognostic model in pancreatic cancer: as key gene.

Wang Z, Fu J, Zhu S, Tang H, Shi K, Yang J Oncol Res. 2024; 32(12):1851-1866.

PMID: 39574475 PMC: 11576954. DOI: 10.32604/or.2024.055286.

References

Zhou X, Lu Z, Wang T, Huang Z, Zhu W, Miao Y . Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. Gene. 2018; 673:181-193. DOI: 10.1016/j.gene.2018.06.037. View

Demas D, Demo S, Fallah Y, Clarke R, Nephew K, Althouse S . Glutamine Metabolism Drives Growth in Advanced Hormone Receptor Positive Breast Cancer. Front Oncol. 2019; 9:686. PMC: 6688514. DOI: 10.3389/fonc.2019.00686. View

Sun Y, Ren D, Yang C, Yang W, Zhao J, Zhou Y . TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation. Biochim Biophys Acta Mol Basis Dis. 2021; 1867(11):166213. DOI: 10.1016/j.bbadis.2021.166213. View

Wang L, Yi X, Xiao X, Zheng Q, Ma L, Li B . Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression. Cell Mol Biol Lett. 2022; 27(1):106. PMC: 9724320. DOI: 10.1186/s11658-022-00406-9. View

Javeed N, Mukhopadhyay D . Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res. 2017; 31(5):386-394. PMC: 5706431. DOI: 10.7555/JBR.30.20150162. View

Lan J, Sun L, Xu F, Liu L, Hu F, Song D . M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer. Cancer Res. 2018; 79(1):146-158. DOI: 10.1158/0008-5472.CAN-18-0014. View

Fan W, Liu X, Ren D . TRIM62 silencing represses the proliferation and invasion and increases the chemosensitivity of hepatocellular carcinoma cells by affecting the NF-κB pathway. Toxicol Appl Pharmacol. 2022; 445:116035. DOI: 10.1016/j.taap.2022.116035. View

Li R, Zhu L, Peng Y, Zhang X, Dai C, Liu D . TRIM50 Suppresses Pancreatic Cancer Progression and Reverses the Epithelial-Mesenchymal Transition Facilitating the Ubiquitous Degradation of Snail1. Front Oncol. 2021; 11:695740. PMC: 8458909. DOI: 10.3389/fonc.2021.695740. View

Sun J, Yan J, Qiao H, Zhao F, Li C, Jiang J . Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation. Oncogene. 2019; 39(3):546-559. DOI: 10.1038/s41388-019-0992-2. View

10.

Yang E, Wang X, Gong Z, Yu M, Wu H, Zhang D . Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression. Signal Transduct Target Ther. 2020; 5(1):242. PMC: 7572387. DOI: 10.1038/s41392-020-00359-5. View

11.

Liu T, Chen J, Shang C, Shen H, Huang J, Liang Y . Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer. J Exp Clin Cancer Res. 2016; 35(1):170. PMC: 5084416. DOI: 10.1186/s13046-016-0445-5. View

12.

Giannone G, Ghisoni E, Genta S, Scotto G, Tuninetti V, Turinetto M . Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy. Int J Mol Sci. 2020; 21(12). PMC: 7352562. DOI: 10.3390/ijms21124414. View

13.

Altman B, Stine Z, Dang C . From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2017; 16(12):773. DOI: 10.1038/nrc.2016.131. View

14.

Jin X, Sun Y, Yang H, Li J, Yu S, Chang X . Deregulation of the MiR-193b-KRAS Axis Contributes to Impaired Cell Growth in Pancreatic Cancer. PLoS One. 2015; 10(4):e0125515. PMC: 4408116. DOI: 10.1371/journal.pone.0125515. View

15.

Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y . Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019; 21(4):498-510. DOI: 10.1038/s41556-019-0299-0. View

16.

Song S, Zhao Y, Wang X, Tong X, Chen X, Xiong Q . M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6. Biol Chem. 2022; 404(1):41-57. DOI: 10.1515/hsz-2022-0162. View

17.

Quintas-Cardama A, Post S, Solis L, Xiong S, Yang P, Chen N . Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer. J Pathol. 2014; 234(1):108-19. PMC: 4138305. DOI: 10.1002/path.4385. View

18.

Zhao Z, Liu W . Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment. Technol Cancer Res Treat. 2020; 19:1533033820962117. PMC: 7768873. DOI: 10.1177/1533033820962117. View

19.

Cao Z, Conway K, Heath R, Rush J, Leshchiner E, Ramirez-Ortiz Z . Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. Immunity. 2015; 43(4):715-26. PMC: 4672733. DOI: 10.1016/j.immuni.2015.10.005. View

20.

Schmidt F, Kny M, Zhu X, Wollersheim T, Persicke K, Langhans C . The E3 ubiquitin ligase TRIM62 and inflammation-induced skeletal muscle atrophy. Crit Care. 2014; 18(5):545. PMC: 4231194. DOI: 10.1186/s13054-014-0545-6. View