Abstract
Introduction: Acute lymphoblastic leukemia (ALL) is a common hematologic neoplastic disease. This study discussed the effect of extracellular vesicles (EVs) released from bone marrow mesenchymal stem cells (BMSCs) on ALL cells and the mechanism. Methods: BMSCs-EVs were isolated by differential centrifugation and identified. The effect of BMSCs-EVs on ALL cell proliferation and apoptosis was evaluated. The expression of miR-29b-3p in ALL cells and EVs was detected. The uptake of EVs by ALL cells was observed. The effect of miR-29b-3p on ALL cell proliferation and apoptosis was assessed after silencing miR-29b-3p. The targeting relation of miR-29b-3p and GDF15 was analyzed by bioinformatics website and dual-luciferase assay. The role of GDF15 in proliferation and apoptosis of ALL cells was further confirmed, and Western blot assay was performed to measure MAPK pathway-related protein levels. Results: BMSC-derived EVs inhibited proliferation and promoted apoptosis of ALL cells, as shown by the up-regulation of caspase-3 and Bax expressions and down-regulation of Bcl-2 expression. EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p expression in ALL cells, and inhibited GDF15 expression. Silencing of miR-29b-3p or overexpression of GDF15 partially reversed the effect of EVs. EVs inhibited the MAPK pathway through the miR-29b-3p/GDF15 axis. Conclusion: BMSCs-EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p, and inhibited GDF15 to suppress the MAPK pathway and further inhibit proliferation and promote apoptosis of ALL cells.
References
1.
Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020;395(10230):1146–62.
2.
Vrooman LM, Silverman LB. Treatment of childhood acute lymphoblastic leukemia: prognostic factors and clinical advances. Curr Hematol Malig Rep. 2016;11(5):385–94.
3.
Chen YL, Tang C, Zhang MY, Huang WL, Xu Y, Sun HY, et al. Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia. Leukemia. 2019;33(10):2365–78.
4.
Matsukura T, Inaba C, Weygant EA, Kitamura D, Janknecht R, Matsumoto H, et al. Extracellular vesicles from human bone marrow mesenchymal stem cells repair organ damage caused by cadmium poisoning in a medaka model. Physiol Rep. 2019;7(14):e14172.
5.
Mudgapalli N, Nallasamy P, Chava H, Chava S, Pathania AS, Gunda V, et al. The role of exosomes and MYC in therapy resistance of acute myeloid leukemia: challenges and opportunities. Mol Aspects Med. 2019;70:21–32.
6.
Deng W, Wang L, Pan M, Zheng J. The regulatory role of exosomes in leukemia and their clinical significance. J Int Med Res. 2020;48(8):0300060520950135.
7.
Liu Y, Song B, Wei Y, Chen F, Chi Y, Fan H, et al. Exosomes from mesenchymal stromal cells enhance imatinib-induced apoptosis in human leukemia cells via activation of caspase signaling pathway. Cytotherapy. 2018;20(2):181–8.
8.
Pando A, Reagan JL, Quesenberry P, Fast LD. Extracellular vesicles in leukemia. Leuk Res. 2018;64:52–60.
9.
Zhang F, Lu Y, Wang M, Zhu J, Li J, Zhang P, et al. Exosomes derived from human bone marrow mesenchymal stem cells transfer miR-222-3p to suppress acute myeloid leukemia cell proliferation by targeting IRF2/INPP4B. Mol Cell Probes. 2020;51:101513.
10.
Zhuang M, Chaolumen Q, Li L, Chen B, Su Q, Yang Y, et al. MiR-29b-3p cooperates with miR-29c-3p to affect the malignant biological behaviors in T-cell acute lymphoblastic leukemia via TFAP2C/GPX1 axis. Biochem Biophys Res Commun. 2020;527(2):511–7.
11.
Donnelly SM, Paplomata E, Peake BM, Sanabria E, Chen Z, Nahta R. P38 MAPK contributes to resistance and invasiveness of HER2- overexpressing breast cancer. Curr Med Chem. 2013;21(4):501–10.
12.
Shimizu S, Kadowaki M, Yoshioka H, Kambe A, Watanabe T, Kinyamu HK, et al. Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells. Biochem Biophys Res Commun. 2013;430(4):1277–82.
13.
Li H, Dong C, Tian Y, Li X, Wang B, Zhai D, et al. Knockdown of diacylglycerol kinase zeta (DGKZ) induces apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells through MAPK/survivin/caspase pathway. Pharmazie. 2019;74(7):418–22.
14.
Shukla A, Shukla V, Joshi SS. Regulation of MAPK signaling and implications in chronic lymphocytic leukemia. Leuk Lymphoma. 2018;59(7):1565–73.
15.
Ji Z, Wang C, Tong Q. Role of miRNA-324-5p-modified adipose-derived stem cells in post-myocardial infarction repair. Int J Stem Cell. 2021;14(3):298–309.
16.
Duan S, Wang F, Cao J, Wang C. Exosomes derived from MicroRNA-146a-5p-enriched bone marrow mesenchymal stem cells alleviate intracerebral hemorrhage by inhibiting neuronal apoptosis and microglial M1 polarization. Drug Des Devel Ther. 2020;14:3143–58.
17.
Sekiya I, Vuoristo JT, Larson BL, Prockop DJ. In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc Natl Acad Sci U S A. 2002;99(7):4397–402.
18.
Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22.
19.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402–8.
20.
Jasek-Gajda E, Jurkowska H, Jasinska M, Lis GJ. Targeting the MAPK/ERK and PI3K/AKT signaling pathways affects NRF2, trx and GSH antioxidant systems in leukemia cells. Antioxidants. 2020;9(7):633.
21.
Haque S, Vaiselbuh SR. CD19 chimeric antigen receptor-exosome targets CD19 positive B-lineage acute lymphocytic leukemia and induces cytotoxicity. Cancers. 2021;13(6):1401.
22.
Mitchell R, Mellows B, Sheard J, Antonioli M, Kretz O, Chambers D, et al. Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins. Stem Cell Res Ther. 2019;10(1):116.
23.
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther. 2018;9(1):63.
24.
Vakhshiteh F, Atyabi F, Ostad SN. Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy. Int J Nanomedicine. 2019;14:2847–59.
25.
Abbaszade Dibavar M, Soleimani M, Atashi A, Rassaei N, Amiri S. The effect of simultaneous administration of arsenic trioxide and microvesicles derived from human bone marrow mesenchymal stem cells on cell proliferation and apoptosis of acute myeloid leukemia cell line. Artif Cell Nanomed Biotechnol. 2018;46(Suppl 3):S138–46.
26.
Ji D, He Y, Lu W, Rong Y, Li F, Huang X, et al. Small-sized extracellular vesicles (EVs) derived from acute myeloid leukemia bone marrow mesenchymal stem cells transfer miR-26a-5p to promote acute myeloid leukemia cell proliferation, migration, and invasion. Hum Cell. 2021;34(3):965–76.
27.
Zahedpanah M, Takanlu JS, Nikbakht M, Rad F, Farhid F, Mousavi SA, et al. Microvesicles of osteoblasts modulate bone marrow mesenchymal stem cell-induced apoptosis to curcumin in myeloid leukemia cells. J Cell Physiol. 2019;234(10):18707–19.
28.
Phetfong J, Tawonsawatruk T, Kamprom W, Ontong P, Tanyong D, Borwornpinyo S, et al. Bone marrow-mesenchymal stem cell-derived extracellular vesicles affect proliferation and apoptosis of leukemia cells in vitro. FEBS Open Bio. 2022;12(2):470–9.
29.
Ji Y, Ma Y, Chen X, Ji X, Gao J, Zhang L, et al. Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibit proliferation of leukemia cells. Oncol Rep. 2017;38(2):1013–20.
30.
Hendijani F, Haghjooy Javanmard S, Sadeghi-aliabadi H. Human Wharton’s jelly mesenchymal stem cell secretome display antiproliferative effect on leukemia cell line and produce additive cytotoxic effect in combination with doxorubicin. Tissue Cell. 2015;47(3):229–34.
31.
Haque S, Vaiselbuh SR. Silencing of exosomal miR-181a reverses pediatric acute lymphocytic leukemia cell proliferation. Pharmaceuticals. 2020;13(9):241.
32.
Xu YC, Lin YS, Zhang L, Lu Y, Sun YL, Fang ZG, et al. MicroRNAs of bone marrow mesenchymal stem cell-derived exosomes regulate acute myeloid leukemia cell proliferation and apoptosis. Chin Med J. 2020;133(23):2829–39.
33.
Lin LP, Zhang Q, Wu W, Xue Y, Tang YJ, Lin DH. Effect of MiR-29b-3p targeting STAT3 on proliferation and apoptosis of acute myeloid leukemia cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2020;28(6):1853–8.
34.
Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A. 1997;94(21):11514–9.
35.
Coppede F, Lopomo A, Spisni R, Migliore L. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol. 2014;20(4):943–56.
36.
Breit SN, Tsai VWW, Brown DA. Targeting obesity and cachexia: identification of the GFRAL receptor-MIC-1/GDF15 pathway. Trends Mol Med. 2017;23(12):1065–7.
37.
Weng PW, Pikatan NW, Setiawan SA, Yadav VK, Fong IH, Hsu CH, et al. Role of GDF15/MAPK14 Axis in chondrocyte senescence as a novel senomorphic agent in osteoarthritis. Int J Mol Sci. 2022;23(13):7043.
38.
Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25(6):778–93.
39.
Zhai Y, Zhang J, Wang H, Lu W, Liu S, Yu Y, et al. Growth differentiation factor 15 contributes to cancer-associated fibroblasts-mediated chemo-protection of AML cells. J Exp Clin Cancer Res. 2016;35(1):147.
40.
Lu W, Wan Y, Li Z, Zhu B, Yin C, Liu H, et al. Growth differentiation factor 15 contributes to marrow adipocyte remodeling in response to the growth of leukemic cells. J Exp Clin Cancer Res. 2018;37(1):66.
41.
Guo Y, Ayers JL, Carter KT, Wang T, Maden SK, Edmond D, et al. Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15. Aging Cell. 2019;18(6):e13013.
42.
Wu SY, Wen YC, Ku CC, Yang YC, Chow JM, Yang SF, et al. Penfluridol triggers cytoprotective autophagy and cellular apoptosis through ROS induction and activation of the PP2A-modulated MAPK pathway in acute myeloid leukemia with different FLT3 statuses. J Biomed Sci. 2019;26(1):63.
43.
Espinoza JL, Elbadry MI, Taniwaki M, Harada K, Trung LQ, Nakagawa N, et al. The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia. Cancer Lett. 2017;400:127–36.
44.
Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjær SB, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017;23(10):1158–66.
45.
Li S, Ma YM, Zheng PS, Zhang P. GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. J Exp Clin Cancer Res. 2018;37(1):80.
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