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Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis

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Abstract

Adipose tissue has long been considered to be involved in tumor progression. However, the adipocyte-secreted molecular determinants that regulate hepatocellular cancer progression have not been defined yet. In this study, the expression pattern of exosome miRNAs in hepatocellular carcinoma (HCC) patients with high body fat ratio (BFR) were identified by using low-density microarray. And the targets of exosome-miRNAs in HCC cells were predicted by bioinformatics methods and verified by in vitro as well as in vivo experiments. Here, we show that microRNA-23a/b (miR-23a/b) was significantly upregulated in both serum exosomes and tumor tissues of HCC patients with a high body fat ratio than low BFR. Subsequently, in vitro studies suggested that miR-23a/b was most likely to be derived from adipocytes and was transported into cancer cells via exosomes, thus promoting HCC cell growth and migration. Meanwhile, exosome miR-23a and miR-23b confer chemoresistance by targeting the von Hippel-Lindau/hypoxia-inducible factor axis. Our study provides evidence in that high BFR-related exosome miR23-a/b is a promising target for future treatment of HCC.

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References

  1. An Y, Zhang Z, Shang Y, Jiang X, Dong J, Yu P, Nie Y, Zhao Q (2015) miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2. Cell Death Dis 6:e1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, Aslam T, Patanwala I, Gaggar S, Cole M, Sumpter K, Stewart S, Rose J, Hudson M, Manas D, Reeves HL (2014) Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 60:110–117

    Article  PubMed  Google Scholar 

  3. Fleshner M, Crane CR (2017) Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol 38:768–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, Lubensky I, Duan DR, Florence C, Pozzatti R, Walther MM, Bander NH, Grossman HB, Brauch H, Pomer S, Brooks JD, Isaacs WB, Lerman MI, Zbar B, Linehan WM (1994) Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 7:85–90

    Article  CAS  PubMed  Google Scholar 

  6. Kuzmin I, Duh FM, Latif F, Geil L, Zbar B, Lerman MI (1995) Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene. Oncogene 10:2185–2194

    CAS  PubMed  Google Scholar 

  7. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320

  8. Liu SJ, Wang JY, Peng SH, Li T, Ning XH, Hong BA, Liu JY, Wu PJ, Zhou BW, Zhou JC, Qi NN, Peng X, Zhang JF, Ma KF, Cai L, Gong K (2018) Genotype and p'henotype correlation in von Hippel-Lindau disease based on alteration of the HIF-alpha binding site in VHL protein. Genet Med 20:1266–1273

    Article  CAS  PubMed  Google Scholar 

  9. Najafi Z, Sharifi M, Javadi G (2019) LNA inhibitor in microRNA miR-23b as a potential anti-proliferative option in human hepatocellular carcinoma. J Gastrointest Cancer. https://doi.org/10.1007/s12029-019-00215-y

  10. Ray K (2013) Gut microbiota: obesity-induced microbial metabolite promotes HCC. Nat Rev Gastroenterol Hepatol 10:442

    Article  PubMed  Google Scholar 

  11. Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578

    Article  CAS  PubMed  Google Scholar 

  12. Sruthi TV, Edatt L, Raji GR, Kunhiraman H, Shankar SS, Shankar V, Ramachandran V, Poyyakkara A, Kumar SVB (2018) Horizontal transfer of miR-23a from hypoxic tumor cell colonies can induce angiogenesis. J Cell Physiol 233:3498–3514

    Article  CAS  PubMed  Google Scholar 

  13. Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, Song J, Li Z, Zhang Z, Yuan W (2018) Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer 17:147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tarade D, Ohh M (2018) The HIF and other quandaries in VHL disease. Oncogene 37:139–147

    Article  CAS  PubMed  Google Scholar 

  15. Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK, Gorden P, Kahn CR (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wendler F, Favicchio R, Simon T, Alifrangis C, Stebbing J, Giamas G (2017) Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention. Oncogene 36:877–884

    Article  CAS  PubMed  Google Scholar 

  17. Yu J, Shen J, Sun TT, Zhang X, Wong N (2013) Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 23:483–491

    Article  CAS  PubMed  Google Scholar 

  18. Yuen JS, Cockman ME, Sullivan M, Protheroe A, Turner GD, Roberts IS, Pugh CW, Werner H, Macaulay VM (2007) The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. Oncogene 26:6499–6508

    Article  CAS  PubMed  Google Scholar 

  19. Zatyka M, da Silva NF, Clifford SC, Morris MR, Wiesener MS, Eckardt KU, Houlston RS, Richards FM, Latif F, Maher ER (2002) Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res 62:3803–3811

    CAS  PubMed  Google Scholar 

  20. Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, Li S, Yang H, Li J, Ning T, Huang D, Li H, Zhang L, Ying G, Ba Y (2017) Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun 8:15016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the Hunan Natural Science Youth Fund Project (Project number: 2018JJ3784. Project name: Molecular mechanism of miR-1181 involvement in promoting proliferation and survival of hepatocellular)

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Authors and Affiliations

  1. Department of Pathology, Infectious Diseases Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

    Yang Liu, Juan Tan & Limin Chen

  2. Medical Oncology Institute, Hunan Cancer Hospital, Changsha, Hunan, China

    Shuangyan Ou

  3. Hunan Polytechnic of Environment and Biology, Hengyang, Hunan, China

    Jun Chen

Authors
  1. Yang Liu
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  2. Juan Tan
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  3. Shuangyan Ou
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  4. Jun Chen
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  5. Limin Chen
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Correspondence to Limin Chen.

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Research involving human participants and/or animals

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Liu, Y., Tan, J., Ou, S. et al. Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis. J Physiol Biochem 75, 391–401 (2019). https://doi.org/10.1007/s13105-019-00692-6

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  • DOI: https://doi.org/10.1007/s13105-019-00692-6

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