Article | Published:

Tumor-derived exosomes promote tumor self-seeding in hepatocellular carcinoma by transferring miRNA-25-5p to enhance cell motility

Oncogenevolume 37pages49644978 (2018) | Download Citation


Tumor self-seeding occurs when circulating malignant cells reinfiltrate the original tumor. The process may breed more aggressive tumor cells, which may contribute to cancer progression. In this study, we observed tumor self-seeding in mouse xenograft models of hepatocellular carcinoma (HCC) for the first time. We confirmed that circulating tumor cell uptake of tumor-derived exosomes, which are increasingly recognized as key instigators of cancer progression by facilitating cell–cell communication, promoted tumor self-seeding by enhancing the invasive and migration capability of recipient HCC cells. Horizontal transfer of exosomal microRNA-25-5p to anoikis-resistant HCC cells significantly enhanced their migratory and invasive abilities, whereas inhibiting microRNA-25-5p alleviated these effects. Our experiments delineate an exosome-based novel pathway employed by functional microRNA from the original tumor cells that can influence the biological fate of circulating tumor cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer. J Int du Cancer. 2015;136:E359–86.

  2. 2.

    Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA. 2012;62:394–9.

  3. 3.

    Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315–26.

  4. 4.

    Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastas Rev. 1989;8:98–101.

  5. 5.

    Dondossola E, Crippa L, Colombo B, Ferrero E, Corti A. Chromogranin A regulates tumor self-seeding and dissemination. Cancer Res. 2011;72:449–59.

  6. 6.

    Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412–20.

  7. 7.

    Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.

  8. 8.

    Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151:1542–56.

  9. 9.

    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.

  10. 10.

    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.

  11. 11.

    Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.

  12. 12.

    Zhang Y, Ma Q, Liu T, Ke S, Jiang K, Wen Y, et al. Tumor self-seeding by circulating tumor cells in nude mouse models of human osteosarcoma and a preliminary study of its mechanisms. J Cancer Res Clin Oncol. 2013;140:329–40.

  13. 13.

    Harris DA, Patel SH, Gucek M, Hendrix A, Westbroek W, Taraska JW. Exosomes released from breast cancer carcinomas stimulate cell movement. PloS One. 2015;10:e0117495.

  14. 14.

    Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc Natl Acad Sci USA. 2014; 111: 711–16.

  15. 15.

    Hendrix A, Westbroek W, Bracke M, De Wever O. An ex(o)citing machinery for invasive tumor growth. Cancer Res. 2010;70:9533–7.

  16. 16.

    Ekstrom EJ, Bergenfelz C, von Bulow V, Serifler F, Carlemalm E, Jonsson G, et al. WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Mol Cancer. 2014;13:88.

  17. 17.

    Mineo M, Garfield SH, Taverna S, Flugy A, De Leo G, Alessandro R, et al. Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion. Angiogenesis. 2012;15:33–45.

  18. 18.

    Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol & Cell Proteom: MCP. 2010;9:1085–99.

  19. 19.

    Lv MM, Zhu XY, Chen WX, Zhong SL, Hu Q, Ma TF, et al. Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumor Biol. 2014;35:10773–9.

  20. 20.

    Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L. Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PloS One. 2011;6:e16899.

  21. 21.

    Janikashvili N, Bonnotte B, Katsanis E, Larmonier N. The dendritic cell-regulatory T lymphocyte crosstalk contributes to tumor-induced tolerance. Clin Dev Immunol. 2011;2011:430394.

  22. 22.

    Zhang ZY, Cao L, Li J, Liang XH, Liu YG, Liu H, et al. Acquisition of anoikis resistance reveals a synoikis-like survival style in BEL7402 hepatoma cells. Cancer Lett. 2008;267:106–15.

  23. 23.

    Izawa I, Nishizawa M, Ohtakara K, Inagaki M. Densin-180 interacts with delta-catenin/neural plakophilin-related armadillo repeat protein at synapses. J Biol Chem. 2002;277:5345–50.

  24. 24.

    Zhang Y, Yeh S, Appleton BA, Held HA, Kausalya PJ, Phua DC, et al. Convergent and divergent ligand specificity among PDZ domains of the LAP and zonula occludens (ZO) families. J Biol Chem. 2006;281:22299–311.

  25. 25.

    Robison AJ, Bass MA, Jiao Y, MacMillan LB, Carmody LC, Bartlett RK, et al. Multivalent interactions of calcium/calmodulin-dependent protein kinase II with the postsynaptic density proteins NR2B, densin-180, and alpha-actinin-2. J Biol Chem. 2005;280:35329–36.

  26. 26.

    Heikkila E, Ristola M, Endlich K, Lehtonen S, Lassila M, Havana M, et al. Densin and beta-catenin form a complex and co-localize in cultured podocyte cell junctions. Mol Cell Biochem. 2007;305:9–18.

  27. 27.

    Zhang H, Zuo Z, Lu X, Wang L, Wang H, Zhu Z. MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep. 2012;27:594–8.

  28. 28.

    Razumilava N, Bronk SF, Smoot RL, Fingas CD, Werneburg NW, Roberts LR, et al. miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology. 2012;55:465–75.

  29. 29.

    Li BS, Zuo QF, Zhao YL, Xiao B, Zhuang Y, Mao XH, et al. MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival. Oncogene. 2015;34:2556–65.

  30. 30.

    Wang C, Wang X, Su Z, Fei H, Liu X, Pan Q. MiR-25 promotes hepatocellular carcinoma cell growth, migration and invasion by inhibiting RhoGDI1. Oncotarget. 2015;6:36231–44.

  31. 31.

    Zhou H, Rigoutsos I. MiR-103a-3p targets the 5’ UTR of GPRC5A in pancreatic cells. RNA. 2014;20:1431–9.

  32. 32.

    Meister G. Argonaute proteins: functional insights and emerging roles. Nat Rev Genet. 2013;14:447–59.

  33. 33.

    Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA. 2011;108:5003–8.

  34. 34.

    Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707–21.

  35. 35.

    McKenzie AJ, Hoshino D, Hong NH, Cha DJ, Franklin JL, Coffey RJ, et al. KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes. Cell Rep. 2016;15:978–87.

  36. 36.

    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.

  37. 37.

    Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;3:Unit 3 22.

Download references


This work was supported by the National Natural Science Foundation of China (No. 81472212), 973 Program of China (No. 2014CB542101), Key Program of Medical Scientific Research Foundation of Zhejiang Province, China (No.WKJ-ZJ-1410), Key Program of Administration of Traditional Chinese Medicine of Zhejiang Province, China (No.2014ZZ007) and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.

Author information


  1. Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    • Hao Liu
    • , Wei Chen
    • , Xiao Zhi
    • , En-Jiang Chen
    • , Tao Wei
    • , Jian Zhang
    • , Jian Shen
    • , Li-Qiang Hu
    • , Xue-Li Bai
    •  & Ting-Bo Liang
  2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China

    • Hao Liu
    • , Wei Chen
    • , Xiao Zhi
    • , En-Jiang Chen
    • , Tao Wei
    • , Jian Zhang
    • , Jian Shen
    • , Li-Qiang Hu
    • , Xue-Li Bai
    •  & Ting-Bo Liang
  3. Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China

    • Bin Zhao
    •  & Xin-Hua Feng


  1. Search for Hao Liu in:

  2. Search for Wei Chen in:

  3. Search for Xiao Zhi in:

  4. Search for En-Jiang Chen in:

  5. Search for Tao Wei in:

  6. Search for Jian Zhang in:

  7. Search for Jian Shen in:

  8. Search for Li-Qiang Hu in:

  9. Search for Bin Zhao in:

  10. Search for Xin-Hua Feng in:

  11. Search for Xue-Li Bai in:

  12. Search for Ting-Bo Liang in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Ting-Bo Liang.

Electronic supplementary material

About this article

Publication history





Issue Date


Further reading