Tumor Biology

, Volume 37, Issue 3, pp 3697–3704 | Cite as

Radiofrequency ablation-increased CXCL10 is associated with earlier recurrence of hepatocellular carcinoma by promoting stemness

  • Yabo Ouyang
  • Kai Liu
  • Meijun Hao
  • Rongling Zheng
  • Chunmiao Zhang
  • Yanning Wu
  • Xiaofeng Zhang
  • Ning Li
  • Jiasheng Zheng
  • Dexi Chen
Original Article


Radiofrequency ablation (RFA) represents a valuable choice in hepatocellular carcinoma (HCC); however, local recurrence of HCC is common after RFA. Here, 20 primary HCC patients treated by RFA were enrolled. Before (termed 0d) and after RFA treatment for 1 and 7 days (termed 1d and 7d, respectively), plasma and noncancerous tissue were collected. ELISA assay showed that plasma C-X-C motif chemokine 10 (CXCL10) was increased in ten patients (type I patients) but decreased in the other 10 patients (type II patients). The mean interval for HCC recurrence in type I patients was less than the mean interval in type II patients. Interestingly, a significant negative correlation between interval for HCC recurrence and fold change of plasma CXCL10 (1d/0d or 7d/0d) was identified, suggesting that RFA-induced CXCL10 is associated with earlier HCC recurrence. Immunofluorescence assay showed that the receptor of CXCL10, chemokine (C-X-C motif) receptor 3 (CXCR3), was significantly increased in type I, but not type II, patients after RFA. In vitro assay demonstrated that CXCL10 stimulus increased the rate of CD133+ cancer stem cells (CSCs) in HepG2 cells by binding to CXCR3 and then inducing c-Myc expression. Many studies have reported that induction of CD133+ CSCs contributes to HCC recurrence. Thus, CXCL10-increased CD133+ CSCs by activating CXCR3/c-Myc pathway might accelerate HCC recurrence after RFA. These data might have potential implications for HCC therapy.


CXCL10 CXCR3 Hepatocellular carcinoma Radiofrequency ablation Cancer stem cell 



Cancer stem cells


C-X-C motif chemokine 10


Chemokine (C-X-C motif) receptor 3


Hepatocellular carcinoma


Mesenchymal stem cells


Radiofrequency ablation



This work was supported by the National Natural Science Foundation of China (812111545), the Twelfth Key Science and Technology Five-Year Plan of China (2012ZX10001-002, 2012ZX10001-003, and 2012ZX10001-004), the National Key Technology Support Program of China (2012BAI15B08), the Capital Health Research and Development Special (2014-1-1151), and the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality (IDHT20150502).

Conflicts of interest



  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Park EK, Kim HJ, Kim CY, Hur YH, Koh YS, Kim JC, et al. A comparison between surgical resection and radiofrequency ablation in the treatment of hepatocellular carcinoma. Ann Surg Treat Res. 2014;87:72–80.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer. 2012;12:133–43.PubMedGoogle Scholar
  4. 4.
    Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132:2542–56.CrossRefPubMedGoogle Scholar
  5. 5.
    Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27:1749–58.CrossRefPubMedGoogle Scholar
  6. 6.
    Wilson GS, Hu Z, Duan W, Tian A, Wang XM, McLeod D, et al. Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells. Stem Cells Dev. 2013;22:2655–64.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee TK, Cheung VC, Ng IO. Liver tumor-initiating cells as a therapeutic target for hepatocellular carcinoma. Cancer Lett. 2013;338:101–09.CrossRefPubMedGoogle Scholar
  8. 8.
    Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 2013;57:1458–68.CrossRefPubMedGoogle Scholar
  9. 9.
    Charles ED, Dustin LB. Chemokine antagonism in chronic hepatitis C virus infection. J Clin Invest. 2011;121:25–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (review). Oncol Lett. 2011;2:583–89.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA. Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer. 2006;42:768–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Shi M, Guo RP, Zhang CQ, Zhong C, Lin XJ, Li JQ. Expression of CXCR3 in hepatocellular carcinoma. Ai Zheng. 2006;25:1232–37.PubMedGoogle Scholar
  13. 13.
    Liu K, Zhang Y, Hu S, Yu Y, Yang Q, Jin D, et al. Increased levels of BAFF and APRIL related to human active pulmonary tuberculosis. Plos One. 2012;7, e38429.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Liu K, Shi Y, Guo X, Wang S, Ouyang Y, Hao M, et al. CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing Beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2. Cell Death Dis. 2014;5, e1323.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cao L, Zhou Y, Zhai B, Liao J, Xu W, Zhang R, et al. Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines. BMC Gastroenterol. 2011;11:71.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21:283–96.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, et al. C-Myc is required for maintenance of glioma cancer stem cells. Plos One. 2008;3, e3769.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lee EY, Lee ZH, Song YW. CXCL10 and autoimmune diseases. Autoimmun Rev. 2009;8:379–83.CrossRefPubMedGoogle Scholar
  19. 19.
    Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes. Eur J Immunol. 2007;37:338–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Kanda N, Watanabe S. Prolactin enhances interferon-gamma-induced production of CXC ligand 9 (CXCL9), CXCL10, and CXCL11 in human keratinocytes. Endocrinology. 2007;148:2317–25.CrossRefPubMedGoogle Scholar
  21. 21.
    Mee JB, Johnson CM, Morar N, Burslem F, Groves RW. The psoriatic transcriptome closely resembles that induced by interleukin-1 in cultured keratinocytes: dominance of innate immune responses in psoriasis. Am J Pathol. 2007;171:32–42.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Brownell J, Polyak SJ. Molecular pathways: hepatitis C virus, CXCL10, and the inflammatory road to liver cancer. Clin Cancer Res. 2013;19:1347–52.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ling CC, Ng KT, Shao Y, Geng W, Xiao JW, Liu H, et al. Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol. 2014;60:103–09.CrossRefPubMedGoogle Scholar
  24. 24.
    Chaturvedi P, Gilkes DM, Wong CC, Luo W, Zhang H, Wei H, et al. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest. 2013;123:189–205.CrossRefPubMedGoogle Scholar
  25. 25.
    Donega V, Nijboer CH, Braccioli L, Slaper-Cortenbach I, Kavelaars A, van Bel F, et al. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions. Plos One. 2014;9, e112339.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chaturvedi P, Gilkes DM, Takano N, Semenza GL. Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci U S A. 2014;111:E2120–29.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Maru SV, Holloway KA, Flynn G, Lancashire CL, Loughlin AJ, Male DK, et al. Chemokine production and chemokine receptor expression by human glioma cells: role of CXCL10 in tumour cell proliferation. J Neuroimmunol. 2008;199:35–45.CrossRefPubMedGoogle Scholar
  28. 28.
    Lo BK, Yu M, Zloty D, Cowan B, Shapiro J, McElwee KJ. CXCR3/ligands are significantly involved in the tumorigenesis of basal cell carcinomas. Am J Pathol. 2010;176:2435–46.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Giuliani N, Bonomini S, Romagnani P, Lazzaretti M, Morandi F, Colla S, et al. CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival. Haematologica. 2006;91:1489–97.PubMedGoogle Scholar
  30. 30.
    Li Y, Reader JC, Ma X, Kundu N, Kochel T, Fulton AM. (2014) Divergent roles of CXCR3 isoforms in promoting cancer stem-like cell survival and metastasis. Breast Cancer Res Treat.Google Scholar
  31. 31.
    Murphy MJ, Wilson A, Trumpp A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 2005;15:128–37.CrossRefPubMedGoogle Scholar
  32. 32.
    Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell. 2008;2:333–44.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yabo Ouyang
    • 1
    • 2
  • Kai Liu
    • 1
    • 2
  • Meijun Hao
    • 1
  • Rongling Zheng
    • 1
    • 2
  • Chunmiao Zhang
    • 1
    • 2
  • Yanning Wu
    • 1
    • 2
  • Xiaofeng Zhang
    • 1
    • 2
  • Ning Li
    • 1
    • 2
  • Jiasheng Zheng
    • 1
  • Dexi Chen
    • 1
    • 2
  1. 1.Beijing You’an HospitalCapital Medical UniversityBeijingChina
  2. 2.Beijing Institute of HepatologyBeijingChina

Personalised recommendations