M2 Macrophage Derived Extracellular Vesicle-Mediated Transfer of MiR-186-5p Promotes Colon Cancer Progression by Targeting DLC1

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2022 Mar 14

PMID 35280693

Authors

Junfeng Guo

Xingyu Wang

Qingdong Guo

Shengtao Zhu

Peng Li

Shutian Zhang

Li Min

Affiliations

Soon will be listed here.

Abstract

Colon cancer (CC) is one of the most common malignances in digestive tract. M2-polarized macrophages within the tumor microenvironment could facilitate CC cell growth by transferring molecules via extracellular vesicles, but the mechanisms are not fully elucidated. The current study aims to identify the possible effectors in M2 macrophage-derived extracellular vesicles (M2-EVs) and reveal related molecular mechanisms. In our study, we validated the promotion effects of M2-EVs on the proliferation and motility of CC cells, which was found to be dependent on the EVs enclosed molecules by a mild EVs digestion assay. Then we found that miR-186-5p was enriched in M2-EVs and was responsible for the tumor promoting functions of M2-EVs. Furthermore, mechanism investigation revealed M2-EVs transferring miR-186-5p inhibited DLC1 expression by targeting its 3'UTR, and restored DLC1 successfully neutralized the tumor-promoting effects of M2-EVs transferring miR-186-5p via inhibiting the β-catenin pathway. Our study revealed that M2-EVs facilitates the growth and motility of CC cells by delivering the enclosed miR-186-5p, which directly targets DLC1 mRNAs and facilitates their degradation, which could provide a potential biomarker and therapeutic target for CC.

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.

Systemic immune profiling analysis identifying M2-TAM related genes predicted colon cancer prognosis and chemotherapy responses.

Liu X, Liu D, Tan C, Wang J Medicine (Baltimore). 2025; 103(52):e40979.

PMID: 39969348 PMC: 11688056. DOI: 10.1097/MD.0000000000040979.

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.

Apoptotic breast cancer cells after chemotherapy induce pro-tumour extracellular vesicles via LAP-competent macrophages.

Zhang Q, Liu X, Wei Q, Xiong S, Luo W, Zhou Y Redox Biol. 2025; 80:103485.

PMID: 39756316 PMC: 11758215. DOI: 10.1016/j.redox.2024.103485.

Extracellular vesicles and macrophages in tumor microenvironment: Impact on cervical cancer.

Guo W, Liu W, Wang J, Fan X Heliyon. 2024; 10(15):e35063.

PMID: 39165926 PMC: 11334669. DOI: 10.1016/j.heliyon.2024.e35063.

References

Wei L, Murphy B, Wu G, Parker M, Easton J, Gilbertson R . Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget. 2017; 8(39):64685-64697. PMC: 5630286. DOI: 10.18632/oncotarget.19642. View

Solomon D, Kim T, Diaz-Martinez L, Fair J, Elkahloun A, Harris B . Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science. 2011; 333(6045):1039-43. PMC: 3374335. DOI: 10.1126/science.1203619. View

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

Quail D, Joyce J . Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19(11):1423-37. PMC: 3954707. DOI: 10.1038/nm.3394. View

Zhou C, Ma J, Huang L, Yi H, Zhang Y, Wu X . Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1. Oncogene. 2018; 38(8):1256-1268. PMC: 6363643. DOI: 10.1038/s41388-018-0511-x. View

Rahal O, Wolfe A, Mandal P, Larson R, Tin S, Jimenez C . 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(4):1034-1043. DOI: 10.1016/j.ijrobp.2017.11.043. View

Yin G, Zhang B, Li J . miR‑221‑3p promotes the cell growth of non‑small cell lung cancer by targeting p27. Mol Med Rep. 2019; 20(1):604-612. PMC: 6580017. DOI: 10.3892/mmr.2019.10291. View

Chen Y, Zhang S, Wang Q, Zhang X . Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol. 2017; 10(1):36. PMC: 5286803. DOI: 10.1186/s13045-017-0408-0. View

Pinto M, Rios E, Duraes C, Ribeiro R, Machado J, Mantovani A . The Two Faces of Tumor-Associated Macrophages and Their Clinical Significance in Colorectal Cancer. Front Immunol. 2019; 10:1875. PMC: 6710360. DOI: 10.3389/fimmu.2019.01875. View

10.

Feng H, Zhang Z, Qing X, French S, Liu D . miR-186-5p promotes cell growth, migration and invasion of lung adenocarcinoma by targeting PTEN. Exp Mol Pathol. 2019; 108:105-113. DOI: 10.1016/j.yexmp.2019.04.007. View

11.

Vitale I, Manic G, Coussens L, Kroemer G, Galluzzi L . Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019; 30(1):36-50. DOI: 10.1016/j.cmet.2019.06.001. View

12.

Jones D, Schmidt M, Suman S, Hobbing K, Barve S, Gobejishvili L . Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells. BMC Cancer. 2018; 18(1):421. PMC: 5899400. DOI: 10.1186/s12885-018-4258-0. View

13.

Sawa-Wejksza K, Dudek A, Lemieszek M, Kalawaj K, Kandefer-Szerszen M . Colon cancer-derived conditioned medium induces differentiation of THP-1 monocytes into a mixed population of M1/M2 cells. Tumour Biol. 2018; 40(9):1010428318797880. DOI: 10.1177/1010428318797880. View

14.

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

15.

Nemeth A, Orgovan N, Sodar B, Osteikoetxea X, Paloczi K, Szabo-Taylor K . Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA. Sci Rep. 2017; 7(1):8202. PMC: 5557920. DOI: 10.1038/s41598-017-08392-1. View

16.

Zheng X, Liu J, Li X, Tian R, Shang K, Dong X . Angiogenesis is promoted by exosomal DPP4 derived from 5-fluorouracil-resistant colon cancer cells. Cancer Lett. 2020; 497:190-201. DOI: 10.1016/j.canlet.2020.10.009. View

17.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

18.

Binenbaum Y, Fridman E, Yaari Z, Milman N, Schroeder A, David G . Transfer of miRNA in Macrophage-Derived Exosomes Induces Drug Resistance in Pancreatic Adenocarcinoma. Cancer Res. 2018; 78(18):5287-5299. DOI: 10.1158/0008-5472.CAN-18-0124. View

19.

Osteikoetxea X, Sodar B, Nemeth A, Szabo-Taylor K, Paloczi K, Vukman K . Differential detergent sensitivity of extracellular vesicle subpopulations. Org Biomol Chem. 2015; 13(38):9775-82. DOI: 10.1039/c5ob01451d. View

20.

Hoshino A, Costa-Silva B, Shen T, Rodrigues G, Hashimoto A, Mark M . Tumour exosome integrins determine organotropic metastasis. Nature. 2015; 527(7578):329-35. PMC: 4788391. DOI: 10.1038/nature15756. View