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Exosome-mediated transfer of lncRUNX2-AS1 from multiple myeloma cells to MSCs contributes to osteogenesis

Oncogene volume 37, pages 5508–5519 (2018)Cite this article

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Abstract

Multiple myeloma (MM) is characterized by the decreased osteogenic potential of mesenchymal stem cells (MSCs). Communication between cancer cells and cancer stromal cells is a driving factor in tumor progression. Understanding the myeloma–stroma interactions is critical to the development of effective strategies that can reverse bone diseases. Here we identified that bioactive lncRNA RUNX2-AS1 in myeloma cells could be packed into exosomes and transmitted to MSCs, thus repressing the osteogenesis of MSCs. RUNX2-AS1, which arises from the antisense strand of RUNX2, was enriched in MSCs derived from MM patients (MM-MSCs). RUNX2-AS1 was capable of forming an RNA duplex with RUNX2 pre-mRNA at overlapping regions and this duplex transcriptionally repressed RUNX2 expression by reducing the splicing efficiency, resulting in decreased osteogenic potential of MSCs. In vivo mouse models, administered an inhibitor of exosome secretion, GW4869, was found to be effective in preventing bone loss, sustained by both bone formation and anticatabolic activities. Therefore, exosomal lncRNA RUNX2-AS1 may serve as a potential therapeutic target for bone lesions in MM. In summary, our results indicated a key role of exosomal lncRUNX2-AS1 in transferring from MM cells to MSCs in osteogenic differentiation, through a unique exosomal lncRUNX2-AS1/RUNX2 pathway.

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References

  1. Giuliani N, Rizzoli V, Roodman GD. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood. 2006;108:3992–6.

    Article  CAS  Google Scholar 

  2. Raje N, Roodman GD. Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res. 2011;17:1278–86.

    Article  CAS  Google Scholar 

  3. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;29:653–68.

    Article  CAS  Google Scholar 

  4. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499–513.

    Article  CAS  Google Scholar 

  5. Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015;107:djv135.

    Article  Google Scholar 

  6. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25:501–15.

    Article  CAS  Google Scholar 

  7. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest. 2013;123:1542–55.

    Article  CAS  Google Scholar 

  8. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30:1556–64.

    Article  CAS  Google Scholar 

  9. Lokody I. Cancer genetics: exosomally derived miR-105 destroys tight junctions. Nat Rev Genet. 2014;15:362.

    Article  Google Scholar 

  10. Luga V, Wrana JL. Tumor-stroma interaction: Revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res. 2013;73:6843–7.

    Article  CAS  Google Scholar 

  11. Gezer U, Ozgur E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38:1076–9.

    CAS  PubMed  Google Scholar 

  12. Mohankumar S, Patel T. Extracellular vesicle long noncoding RNA as potential biomarkers of liver cancer. Brief Funct Genom. 2015;15:249–56.

    Article  Google Scholar 

  13. Li Q, Shao Y, Zhang X, Zheng T, Miao M, Qin L, et al. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. Tumour Biol. 2015;36:2007–12.

    Article  CAS  Google Scholar 

  14. Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.

    Article  CAS  Google Scholar 

  15. He C, Sidoli S, Warneford-Thomson R, Tatomer DC, Wilusz JE, Garcia BA, et al. High-resolution mapping of RNA-binding regions in the nuclear proteome of embryonic stem cells. Mol Cell. 2016;64:416–30.

    Article  CAS  Google Scholar 

  16. Hudson WH, Pickard MR, de Vera IM, Kuiper EG, Mourtada-Maarabouni M, Conn GL, et al. Conserved sequence-specific lincRNA-steroid receptor interactions drive transcriptional repression and direct cell fate. Nat Commun. 2014;5:5395.

    Article  CAS  Google Scholar 

  17. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

    Article  CAS  Google Scholar 

  18. Faghihi MA, Wahlestedt C. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol. 2009;10:637–43.

    Article  CAS  Google Scholar 

  19. Lee JT. Epigenetic regulation by long noncoding RNAs. Science. 2012;338:1435–9.

    Article  CAS  Google Scholar 

  20. Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491:454–7.

    Article  CAS  Google Scholar 

  21. Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genom. 2013;14:319.

    Article  CAS  Google Scholar 

  22. Takahashi K, Yan IK, Wood J, Haga H, Patel T. Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res. 2014;12:1377–87.

    Article  CAS  Google Scholar 

  23. Franceschi RT, Xiao G, Jiang D, Gopalakrishnan R, Yang S, Reith E. Multiple signaling pathways converge on the Cbfa1/Runx2 transcription factor to regulate osteoblast differentiation. Connect Tissue Res. 2003;44(Suppl 1):109–16.

    Article  CAS  Google Scholar 

  24. Komori T. Regulation of skeletal development by the Runx family of transcription factors. J Cell Biochem. 2005;95:445–53.

    Article  CAS  Google Scholar 

  25. Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, et al. Antisense transcription in the mammalian transcriptome. Science. 2005;309:1564–6.

    Article  Google Scholar 

  26. Wahlestedt C. Natural antisense and noncoding RNA transcripts as potential drug targets. Drug Discov Today. 2006;11:503–8.

    Article  CAS  Google Scholar 

  27. He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW. The antisense transcriptomes of human cells. Science. 2008;322:1855–7.

    Article  CAS  Google Scholar 

  28. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221–30.

    Article  CAS  Google Scholar 

  29. Fabbri M,Paone A,Calore F,Galli R,Gaudio E,Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA. 2012;109:E2110–6.

    Article  CAS  Google Scholar 

  30. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285:17442–52.

    Article  CAS  Google Scholar 

  31. Zhuang W, Ge X, Yang S, Huang M, Zhuang W, Chen P, et al. Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription. Stem Cells. 2015;33:1985–97.

    Article  CAS  Google Scholar 

  32. Li B, Shi M, Li J, Zhang H, Chen B, Chen L, et al. Elevated tumor necrosis factor-alpha suppresses TAZ expression and impairs osteogenic potential of Flk-1+mesenchymal stem cells in patients with multiple myeloma. Stem Cells Dev. 2007;16:921–30.

    Article  CAS  Google Scholar 

  33. Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36:4929–42.

    Article  CAS  Google Scholar 

  34. Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, et al. Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun. 2015;6:6999.

    Article  CAS  Google Scholar 

  35. Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27:370–81.

    Article  CAS  Google Scholar 

  36. Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344:310–3.

    Article  CAS  Google Scholar 

  37. Scarola M, Comisso E, Pascolo R, Chiaradia R, Marion RM, Schneider C, et al. Epigenetic silencing of Oct4 by a complex containing SUV39H1 and Oct4 pseudogene lncRNA. Nat Commun. 2015;6:7631.

    Article  Google Scholar 

  38. Lister N, Shevchenko G, Walshe JL, Groen J, Johnsson P, Vidarsdottir L, et al. The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene. Proc Natl Acad Sci USA. 2017;114:9942–7.

    Article  CAS  Google Scholar 

  39. Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;2:666–81.

    Article  Google Scholar 

  40. Saldana-Meyer R, Gonzalez-Buendia E, Guerrero G, Narendra V, Bonasio R, Recillas-Targa F, et al. CTCF regulates the human p53 gene through direct interaction with its natural antisense transcript, Wrap53. Genes & Dev. 2014;28:723–34.

    Article  CAS  Google Scholar 

  41. Guo J, Cheng P, Yuan H, Liu Y. The exosome regulates circadian gene expression in a posttranscriptional negative feedback loop. Cell. 2009;138:1236–46.

    Article  CAS  Google Scholar 

  42. Shah S, Wittmann S, Kilchert C, Vasiljeva L. lncRNA recruits RNAi and the exosome to dynamically regulate pho1 expression in response to phosphate levels in fission yeast. Genes Dev. 2014;28:231–44.

    Article  CAS  Google Scholar 

  43. Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MA, Sadek P, Sie D, et al. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 2014;8:1649–58.

    Article  CAS  Google Scholar 

  44. Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, Ri S, Schekman R. Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife. 2016;5:e19276.

    Article  Google Scholar 

  45. 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 USA. 2005;102:15545–50.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by National Natural Science Foundation of China (81673448, 81670191), Natural Science Foundation of Jiangsu Province China (BK 20161218, BK20161223), The Applied Basic Research Programs of Suzhou City (SYS201546), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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    Authors and Affiliations

    1. Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou, China

      Bingzong Li & Yating Hong

    2. Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China

      Hongxia Xu, Huiying Han, Sha Song, Xiaojuan Zhang, Lu Ouyang, Yingchun Qiu, Wenqi Zhou & Wenzhuo Zhuang

    3. Department of Bioinformatics, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China

      Chen’ao Qian & Moli Huang

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    Li, B., Xu, H., Han, H. et al. Exosome-mediated transfer of lncRUNX2-AS1 from multiple myeloma cells to MSCs contributes to osteogenesis. Oncogene 37, 5508–5519 (2018). https://doi.org/10.1038/s41388-018-0359-0

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