Journal of Physiology and Biochemistry

, Volume 75, Issue 3, pp 391–401 | Cite as

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

  • Yang Liu
  • Juan Tan
  • Shuangyan Ou
  • Jun Chen
  • Limin ChenEmail author
Original Article


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.


Adipose Exosomes miR-23 HIF HCC 


Funding information

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)

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 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:e1766CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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 60:110–117CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Fleshner M, Crane CR (2017) Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol 38:768–776CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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 458:762–765CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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 7:85–90CrossRefPubMedGoogle Scholar
  6. 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 10:2185–2194PubMedGoogle Scholar
  7. 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 260:1317–1320Google Scholar
  8. 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 20:1266–1273CrossRefPubMedGoogle Scholar
  9. 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.
  10. 10.
    Ray K (2013) Gut microbiota: obesity-induced microbial metabolite promotes HCC. Nat Rev Gastroenterol Hepatol 10:442CrossRefPubMedGoogle Scholar
  11. 11.
    Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551–578CrossRefPubMedGoogle Scholar
  12. 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 233:3498–3514CrossRefPubMedGoogle Scholar
  13. 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 17:147CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tarade D, Ohh M (2018) The HIF and other quandaries in VHL disease. Oncogene 37:139–147CrossRefPubMedGoogle Scholar
  15. 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 542:450–455CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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 36:877–884CrossRefPubMedGoogle Scholar
  17. 17.
    Yu J, Shen J, Sun TT, Zhang X, Wong N (2013) Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 23:483–491CrossRefPubMedGoogle Scholar
  18. 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 26:6499–6508CrossRefGoogle Scholar
  19. 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 62:3803–3811PubMedGoogle Scholar
  20. 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 8:15016CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© University of Navarra 2019

Authors and Affiliations

  1. 1.Department of Pathology, Infectious Diseases InstituteThe Third Xiangya Hospital of Central South UniversityChangshaChina
  2. 2.Medical Oncology InstituteHunan Cancer HospitalChangshaChina
  3. 3.Hunan Polytechnic of Environment and BiologyHengyangChina

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