Bone marrow mesenchymal stem cell-derived exosomal LINC00847 inhibits the proliferation, migration, and invasion of Ewing sarcoma
Background: Ewing sarcoma (ES) is one of the most lethal primary bone tumors with a poor survival rate. Current evidence suggests that extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) loaded with abundant biological functional lncRNAs confer therapeutic benefits against the development of various tumors.
Aim: This study aimed to investigate the role of exosomal lncRNAs from BMSCs in the pathogenesis of ES.
Methods: Bioinformatic analysis and qRT-PCR experiments were used to detect the expression level of LINC00847 in ES tissues and cells. Cell biology experiments examined the effect of in vitro proliferation, migration, and invasion abilities and the biological function of BMSCs-derived LINC00847. Finally, we constructed a LINC00847-associated competitive endogenous RNA (ceRNA) network by in silico methods. Gene Set Enrichment Analysis (GSEA) was conducted to reveal the potential molecular mechanism of LINC00847.
Results: We found that LINC00847 was markedly downregulated in ES. Overexpression of LINC00847 inhibited ES cell proliferation, migration, and invasion. Furthermore, BMSCs-derived EVs inhibited the proliferation, migration, and invasion of ES cells by delivering LINC00847. We constructed a LINC00847 related-ceRNA network contains five miRNAs (miR-18a-5p, miR-18b-5p, miR-181a-5p, miR-181c-5p, and miR-485-3p) and four mRNAs (GFPT1, HIF1A, NEDD9, and NOTCH2).
Conclusions: Overall, this study found that BMSCs-EVs-derived exosomal LINC00847 inhibited ES cell proliferation, migration, and invasion. The ceRNA regulatory mechanism of LINC00847 may participate in the pathogenesis of the malignant phenotype of Ewing sarcoma.
Relevance for patients: These findings suggest that BMSCs-derived exosomal lncRNAs may be used for the personalized treatment of tumors, providing a novel theoretical framework for treating ES.
[1] Xiong J, Wu L, Huang L, Wu C, Liu Z, Deng W, et al. Lncrna Foxp4-as1 Promotes Progression of Ewing Sarcoma and is Associated with Immune Infiltrates. Front Oncol 2021;11:718876.
[2] Xu J, Zhang Z, Huang L, Xiong J, Zhou Z, Yu H, et al. Let-7a Suppresses Ewing Sarcoma CSCs’ Malignant Phenotype Via Forming a Positive Feedback Circuit with STAT3 and Lin28. J Bone Oncol 2021;31:100406.
[3] Riggi N, Suva ML, Stamenkovic I. Ewing’s Sarcoma. N Engl J Med 2021;384:154-64.
[4] Grunewald TG, Cidre-Aranaz F, Surdez D, Tomazou EM, de Alava E, Kovar H, et al. Ewing Sarcoma. Nat Rev Dis Primers 2018;4:5.
[5] Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, et al. Mesenchymal Stem Cells as a Double-Edged Sword in Tumor Growth: Focusing on MSC-Derived Cytokines. Cell Mol Biol Lett 2021;26:3.
[6] Montazersaheb S, Fathi E, Mamandi A, Farahzadi R, Heidari HR. Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for Therapeutic Interventions. Curr Drug Targets 2022;23:60-71.
[7] Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal Stem Cell Perspective: Cell Biology to Clinical Progress. NPJ Regen Med 2019;4:22.
[8] Jafari A, Rezaei-Tavirani M, Farhadihosseinabadi B, Zali H, Niknejad H. Human Amniotic Mesenchymal Stem Cells to Promote/Suppress Cancer: Two Sides of the Same Coin. Stem Cell Res Ther 2021;12:126.
[9] Aravindhan S, Ejam SS, Lafta MH, Markov A, Yumashev AV, Ahmadi M. Mesenchymal Stem Cells and Cancer Therapy: Insights into Targeting the Tumour Vasculature. Cancer Cell Int 2021;21:158.
[10] Golinelli G, Grisendi G, Dall’Ora M, Casari G, Spano C, Talami R, et al. Anti-gd2 CAR MSCs Against Metastatic Ewing’s Sarcoma. Transl Oncol 2022;15:101240.
[11] Zhang F, Guo J, Zhang Z, Qian Y, Wang G, Duan M, et al. Mesenchymal Stem Cell-Derived Exosome: A Tumor Regulator and Carrier for Targeted Tumor Therapy. Cancer Lett 2022;526:29-40.
[12] Shojaei S, Hashemi SM, Ghanbarian H, Salehi M, Mohammadi-Yeganeh S. Effect of Mesenchymal Stem Cells-Derived Exosomes on Tumor Microenvironment: Tumor Progression Versus Tumor Suppression. J Cell Physiol 2019;234:3394-409.
[13] Gandham S, Su X, Wood J, Nocera AL, Alli SC, Milane L, et al. Technologies and Standardization in Research on Extracellular Vesicles. Trends Biotechnol 2020;38:1066-98.
[14] Moller A, Lobb RJ. The Evolving Translational Potential of Small Extracellular Vesicles in Cancer. Nat Rev Cancer 2020;20:697-709.
[15] Kazimierczyk M, Kasprowicz MK, Kasprzyk ME, Wrzesinski J. Human Long Noncoding RNA Interactome: Detection, Characterization and Function. Int J Mol Sci 2020;21:1027.
[16] Adnane S, Marino A, Leucci E. LncRNAs in Human Cancers: Signal from Noise. Trends Cell Biol 2022;32:565-73.
[17] Liu SJ, Dang HX, Lim DA, Feng FY, Maher CA. Long Noncoding RNAs in Cancer Metastasis. Nat Rev Cancer 2021;21:446-60.
[18] Wang J, Zhang X, Chen W, Hu X, Li J, Liu C. Regulatory Roles of Long Noncoding RNAs Implicated in Cancer Hallmarks. Int J Cancer 2020;146:906-16.
[19] Zhang WL, Liu Y, Jiang J, Tang YJ, Tang YL, Liang XH. Extracellular Vesicle Long Non-Coding RNA-Mediated Crosstalk in the Tumor Microenvironment: Tiny Molecules, Huge Roles. Cancer Sci 2020;111:2726-35.
[20] Pathania AS, Challagundla KB. Exosomal Long Non-Coding RNAs: Emerging Players in the Tumor Microenvironment. Mol Ther Nucleic Acids 2021;23:1371-83.
[21] Da M, Jiang H, Xie Y, Jin W, Han S. The Biological Roles of Exosomal Long Non-Coding RNAs in Cancers. Onco Targets Ther 2021;14:271-87.
[22] Gu H, Yan C, Wan H, Wu L, Liu J, Zhu Z, et al. Mesenchymal Stem Cell-Derived Exosomes Block Malignant Behaviors of Hepatocellular Carcinoma Stem Cells through a LncRNA C5orf66-as1/microRNA-127-3p/ DUSP1/ERK Axis. Hum Cell 2021;34:1812-29.
[23] Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles. Proc Natl Acad Sci U S A 2005;102:15545-50.
[24] Yu G, Wang LG, Han Y, He QY. Clusterprofiler: An R Package for Comparing Biological Themes among Gene Clusters. OMICS 2012;16:284-7.
[25] Li JH, Liu S, Zhou H, Qu LH, Yang JH. Starbase v2.0: Decoding miRNA-Cerna, miRNA-ncRNA and ProteinRNA Interaction Networks from Large-Scale CLIP-Seq Data. Nucleic Acids Res 2014;42:D92-7.
[26] Kang J, Tang Q, He J, Li L, Yang N, Yu S, et al. Rnainter v4.0: RNA Interactome Repository with Redefined Confidence Scoring System and Improved Accessibility. Nucleic Acids Res 2022;50:D326-32.
[27] Chen Y, Wang X. miRDB: An Online Database for Prediction of Functional MicroRNA Targets. Nucleic Acids Res 2020;48:D127-31.
[28] Huang HY, Lin YC, Cui S, Huang Y, Tang Y, Xu J, et al. miRTarBase Update 2022: An Informative Resource for Experimentally Validated miRNA-Target Interactions. Nucleic Acids Res 2022;50:D222-30.
[29] Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005.
[30] McGeary SE, Lin KS, Shi CY, Pham TM, Bisaria N, Kelley GM, et al. The Biochemical Basis of microRNA Targeting Efficacy. Science 2019;366:eaav1741.
[31] Cao Z, Pan X, Yang Y, Huang Y, Shen HB. The LncLocator: A Subcellular Localization Predictor for Long NonCoding RNAs Based on a Stacked Ensemble Classifier. Bioinformatics 2018;34:2185-94.
[32] Wang P, Guo Q, Hao Y, Liu Q, Gao Y, Zhi H, et al. LnCeCell: A Comprehensive Database of Predicted lncRNA-Associated ceRNA Networks at Single-Cell Resolution. Nucleic Acids Res 2021;49:D125-33.
[33] Hesla AC, Papakonstantinou A, Tsagkozis P. Current Status of Management and Outcome for Patients with Ewing Sarcoma. Cancers (Basel) 2021;13:1202.
[34] Tu LR, Li W, Liu J, Song XG, Xu HW. LncRNA LINC00847 Contributes to Hepatocellular Carcinoma Progression byActing as a Sponge of miR-99a to Induce E2F2 Expression. J Biol Regul Homeost Agents 2020;34:2195-203.
[35] Li W, Hu X, Huang X. Long Intergenic Non-Protein Coding RNA 847 Promotes Laryngeal Squamous Cell Carcinoma Progression Through the microRNA-181a-5p/zinc Finger E-box Binding Homeobox 2 Axis. Bioengineered 2022;13:9987-10000.
[36] Li H, Chen YK, Wan Q, Shi AQ, Wang M, He P, et al. Long Non-Coding RNA LINC00847 Induced by E2F1 Accelerates Non-Small Cell Lung Cancer Progression Through Targeting miR-147a/IFITM1 Axis. Front Med (Lausanne) 2021;8:663558.
[37] Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications. Front Cell Dev Biol 2020;8:149.
[38] Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent. Int J Mol Sci 2020;21:727.
[39] Whitford W, Guterstam P. Exosome Manufacturing Status. Future Med Chem 2019;11:1225-36.
[40] Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018): A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines. J Extracell Vesicles 2018;7:1535750.
[41] Zhao W, Qin P, Zhang D, Cui X, Gao J, Yu Z, et al. Long Non-Coding RNA PVT1 Encapsulated in Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promotes Osteosarcoma Growth and Metastasis by Stabilizing ERG and Sponging miR-183-5p. Aging (Albany NY) 2019;11:9581-96.