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Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs

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Tumor Biology

Abstract

While adriamycin (adr) offers improvement in survival for breast cancer (BCa) patients, unfortunately, drug resistance is almost inevitable. Mounting evidence suggests that exosomes act as a vehicle for genetic cargo and constantly shuttle biologically active molecules including microRNAs (miRNAs) between heterogeneous populations of tumor cells, engendering a resistance-promoting niche for cancer progression. Our recent study showed that exosomes from docetaxel-resistance BCa cells could modulate chemosensitivity by delivering miRNAs. Herein, we expand on our previous finding and explore the relevance of exosome-mediated miRNA delivery in resistance transmission of adr-resistant BCa sublines. We now demonstrated the selective packing of miRNAs within the exosomes (A/exo) derived from adr-resistant BCa cells. The highly expressed miRNAs in A/exo were significantly increased in recipient fluorescent sensitive cells (GFP-S) after A/exo incorporation. Gene ontology analysis of predicted targets showed that the top 30 most abundant miRNAs in A/exo were involved in crucial biological processes. Moreover, A/exo not only loaded miRNAs for its production and release but also carried miRNAs associated with Wnt signaling pathway. Furthermore, A/exo co-culture assays indicated that miRNA-containing A/exo was able to increase the overall resistance of GFP-S to adr exposure and regulate gene levels in GFP-S. Our results reinforce our earlier reports that adr-resistant BCa cells could manipulate a more deleterious microenvironment and transmit resistance capacity through altering gene expressions in sensitive cells by transferring specific miRNAs contained within exosomes.

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References

  1. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin. 2014;64:52–62.

    Article  PubMed  Google Scholar 

  2. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.

    Article  CAS  PubMed  Google Scholar 

  3. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32:623–42.

    Article  CAS  PubMed  Google Scholar 

  4. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, et al. Potential role of her2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol. 2012;227:658–67.

    Article  CAS  PubMed  Google Scholar 

  5. O’Brien K, Rani S, Corcoran C, Wallace R, Hughes L, Friel AM, et al. Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. Eur J Cancer (Oxford, England 1990). 2013;49:1845–59.

    Article  Google Scholar 

  6. Bartel DP. Micrornas: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen WX, Zhong SL, Ji MH, Pan M, Hu Q, Lv MM, et al. Micrornas delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer. Tumour Biol J Int Soc Oncod Biol Med. 2014;35:2883–92.

    Article  CAS  Google Scholar 

  8. Chen WX, Cai YQ, Lv MM, Chen L, Zhong SL, Ma TF, et al. Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering micrornas. Tumour Biol J Int Soc Oncod Biol Med. 2014;35:9649–59.

    Article  CAS  Google Scholar 

  9. Li WJ, Zhong SL, Wu YJ, Xu WD, Xu JJ, Tang JH, et al. Systematic expression analysis of genes related to multidrug-resistance in isogenic docetaxel- and adriamycin-resistant breast cancer cell lines. Mol Biol Rep. 2013;40:6143–50.

    Article  CAS  PubMed  Google Scholar 

  10. Zhong S, Li W, Chen Z, Xu J, Zhao J. Mir-222 and mir-29a contribute to the drug-resistance of breast cancer cells. Gene. 2013;531:8–14.

    Article  CAS  PubMed  Google Scholar 

  11. Hu Q, Chen WX, Zhong SL, Zhang JY, Ma TF, Ji H, et al. Microrna-452 contributes to the docetaxel resistance of breast cancer cells. Tumour Biol J Int Soc Oncod Biol Med. 2014;35:6327–34.

    Article  CAS  Google Scholar 

  12. Miot S, Gianni-Barrera R, Pelttari K, Acharya C, Mainil-Varlet P, Juelke H, et al. In vitro and in vivo validation of human and goat chondrocyte labeling by green fluorescent protein lentivirus transduction. Tissue Eng Part C Methods. 2010;16:11–21.

    Article  CAS  PubMed  Google Scholar 

  13. Corcoran C, Rani S, O’Brien K, O’Neill A, Prencipe M, Sheikh R, et al. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One. 2012;7, e50999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jaiswal R, Luk F, Gong J, Mathys JM, Grau GE, Bebawy M. Microparticle conferred microrna profiles—implications in the transfer and dominance of cancer traits. Mol Cancer. 2012;11:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, et al. Transfer of micrornas by embryonic stem cell microvesicles. PLoS One. 2009;4, e4722.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microrna target predictions. Nat Genet. 2005;37:495–500.

    Article  CAS  PubMed  Google Scholar 

  17. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microrna targets. Cell. 2005;120:15–20.

    Article  CAS  PubMed  Google Scholar 

  18. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. Mirbase: tools for microrna genomics. Nucleic Acids Res. 2008;36:D154–8.

    Article  CAS  PubMed  Google Scholar 

  19. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet. 2000;25:25–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. Kegg for linking genomes to life and the environment. Nucleic Acids Res. 2008;36:D480–4.

    Article  CAS  PubMed  Google Scholar 

  21. Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. David bioinformatics resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007;35:W169–75.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Blagodatski A, Poteryaev D, Katanaev VL. Targeting the wnt pathways for therapies. Mol Cell Ther. 2014;2:28.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Polakis P. Wnt signaling in cancer. Cold Spring Harbor perspectives in biology. 2012, 4

  24. Li X, Liu X, Xu W, Zhou P, Gao P, Jiang S, et al. C-myc-regulated mir-23a/24-2/27a cluster promotes mammary carcinoma cell invasion and hepatic metastasis by targeting sprouty2. Hematol J Biol Chem. 2013;288:18121–33.

    Article  CAS  Google Scholar 

  25. Giglio S, Cirombella R, Amodeo R, Portaro L, Lavra L, Vecchione A. Microrna mir-24 promotes cell proliferation by targeting the cdks inhibitors p27kip1 and p16ink4a. J Cell Physiol. 2013;228:2015–23.

    Article  CAS  PubMed  Google Scholar 

  26. Xiao X, Yu S, Li S, Wu J, Ma R, Cao H, et al. Exosomes: decreased sensitivity of lung cancer a549 cells to cisplatin. PLoS One. 2014;9, e89534.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. Exocarta 2012: database of exosomal proteins, rna and lipids. Nucleic Acids Res. 2012;40:D1241–4.

    Article  CAS  PubMed  Google Scholar 

  28. Kosaka N, Iguchi H, Ochiya T. Circulating microrna in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010;101:2087–92.

    Article  CAS  PubMed  Google Scholar 

  29. Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating micrornas into breast cancer cells. Mol Cancer. 2011;10:117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Palma J, Yaddanapudi SC, Pigati L, Havens MA, Jeong S, Weiner GA, et al. Micrornas are exported from malignant cells in customized particles. Nucleic Acids Res. 2012;40:9125–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2 (nsmase2)-dependent exosomal transfer of angiogenic micrornas regulate cancer cell metastasis. J Biol Chem. 2013;288:10849–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, et al. Neuronal exosomal mirna-dependent translational regulation of astroglial glutamate transporter glt1. J Biol Chem. 2013;288:7105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, et al. Unidirectional transfer of microrna-loaded exosomes from t cells to antigen-presenting cells. Nat Commun. 2011;2:282.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ma F, Zhang J, Zhong L, Wang L, Liu Y, Wang Y, et al. Upregulated microrna-301a in breast cancer promotes tumor metastasis by targeting pten and activating wnt/beta-catenin signaling. Gene. 2014;535:191–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge the funding body for supporting this work: the National Natural Science Foundation of China provided to Jin-hai Tang (81272470).

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    Authors and Affiliations

    1. The Fourth Clinical School of Nanjing Medical University, Nanjing, China

      Ling Mao, Jian Li, Wei-xian Chen & Dan-dan Yu

    2. Department of Thyroid and Breast Surgery, Huai’an Second People’s Hospital, Huai’an, China

      Ling Mao

    3. Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China

      Jian Li, Wei-xian Chen, Dan-dan Yu & Jin-hai Tang

    4. Department of Thoracic Surgery, Nanjing Medical University Affiliated Huai’an First People’s Hospital, Huai’an, China

      Yan-qin Cai

    5. Center of Clinical Laboratory, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China

      Shan-liang Zhong & Jian-hua Zhao

    6. Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China

      Jian-wei Zhou

    7. 42 Baiziting, Nanjing, China

      Jian-wei Zhou & Jin-hai Tang

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    1. Ling Mao
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    Ling Mao, Jian Li and Wei-xian Chen contributed equally to this work.

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    Mao, L., Li, J., Chen, Wx. et al. Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs. Tumor Biol. 37, 5247–5256 (2016). https://doi.org/10.1007/s13277-015-4402-2

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    • DOI: https://doi.org/10.1007/s13277-015-4402-2

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