Tumor Biology

, Volume 37, Issue 5, pp 6073–6084 | Cite as

CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment

  • Xin Wan
  • Ci Cheng
  • Qing Shao
  • Zhe Lin
  • Shuai Lu
  • Yun Chen
Original Article

Abstract

CD24 is known as a cell surface molecule in hematopoiesis and also described as a diagnostic marker for tumors. Previous studies suggested the important role of CD24 in hepatocellular carcinoma (HCC) pathogenesis. However, precise functions of CD24 in HCC are still unknown. Here, we found that CD24 is highly expressed in HCC both in mRNA and protein levels. Further, the epithelial-mesenchymal transition (EMT) and Notch1 signaling activations mediated by CD24 were elucidated as potential mechanisms of HCC promotion in Hepa1-6/Hepa1-6-CD24 cell models. Additionally, possible systemic immune reaction was explored through immune cells and Hepa1-6/Hepa1-6-CD24 cell co-culture. We demonstrated that the EMT process of HCC cell was effectively induced by CD24; also, the tumor immune microenvironment was changed by facilitating Notch-related EMT in vivo. These results reveal the underlying link between the HCC processes mediated by CD24. Moreover, as a clear tumor promoter, CD24 is considered a potential new target for HCC treatment.

Keywords

CD24 Epithelial-mesenchymal transition Hepatocellular carcinoma Notch1 Tumor immunity 

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation (30901750, 81272322 to YC), Jiangsu science and technology innovation Program for graduate Research Funds (CXLX13-54 to XW), the Priority Academic Program Development of Jiangsu Higher Education Institutions, Qing Lan Project, Six talent peaks project (JY-018) of Jiangsu Province.

Conflicts of interest

None.

References

  1. 1.
    Springer T, Galfre G, Secher DS, Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978;8:539–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Sagiv E, Arber N. The novel oncogene CD24 and its arising role in the carcinogenesis of the GI tract: from research to therapy. Expert Rev Gastroenterol Hepatol. 2008;2(1):125–33.CrossRefPubMedGoogle Scholar
  3. 3.
    Tan Y, Zhao M, Xiang B, Chang C, Lu Q. CD24: from a hematopoietic differentiation antigen to a genetic risk factor for multiple autoimmune diseases. Clin Rev Allergy Immunol. 2015. doi: 10.1007/s12016-015-8470-2.
  4. 4.
    Liu JQ, Carl Jr JW, Joshi PS, RayChaudhury A, Pu XA, Shi FD, et al. CD24 on the resident cells of the central nervous system enhances experimental autoimmune encephalomyelitis. J Immunol. 2007;178(10):6227–35.Google Scholar
  5. 5.
    Fang X, Zheng P, Tang J, Liu Y. CD24: from A to Z. Cell Mol Immunol. 2010;7(2):100–3.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fujikuni N, Yamamoto H, Tanabe K, Naito Y, Sakamoto N, Tanaka Y, et al. Hypoxia-mediated CD24 expression is correlated with gastric cancer aggressiveness by promoting cell migration and invasion. Cancer Sci. 2014;105(11):1411–20.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Naumov I, Zilberberg A, Shapira S, Avivi D, Kazanov D, Rosin-Arbesfeld R, et al. CD24 knockout prevents colorectal cancer in chemically induced colon carcinogenesis and in APC (Min)/CD24 double knockout transgenic mice. Int J Cancer. 2014;135(5):1048–59.CrossRefPubMedGoogle Scholar
  8. 8.
    Sadot E, Kraus S, Stein M, Naboishchikov I, Toledano O, Kazanov D, et al. CD24 gene polymorphism—a novel prognostic factor in esophageal cancer. Int J Biol Markers. 2014;29(1):e49–54.CrossRefPubMedGoogle Scholar
  9. 9.
    Moulla A, Miliaras D, Sioga A, Kaidoglou A, Economou L. The immunohistochemical expression of CD24 and CD171 adhesion molecules in borderline ovarian tumors. Pol J Pathol. 2013;64(3):180–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Petkova N, Hennenlotter J, Sobiesiak M, Todenhöfer T, Scharpf M, Stenzl A, et al. Surface CD24 distinguishes between low differentiated and transit-amplifying cells in the basal layer of human prostate. Prostate. 2013;73(14):1576–90.Google Scholar
  11. 11.
    Adamczyk A, Niemiec JA, Ambicka A, Mucha-Małecka A, Mituś J, Ryś J. CD44/CD24 as potential prognostic markers in node-positive invasive ductal breast cancer patients treated with adjuvant chemotherapy. J Mol Histol. 2014;45(1):35–45.Google Scholar
  12. 12.
    Ohara Y, Oda T, Sugano M, Hashimoto S, Enomoto T, Yamada K, et al. Histological and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) expression in clinical pancreatic cancer. Cancer Sci. 2013;104(8):1127–34.Google Scholar
  13. 13.
    Buck K, Hug S, Seibold P, Ferschke I, Altevogt P, Sohn C, et al. CD24 polymorphisms in breast cancer: impact on prognosis and risk. Breast Cancer Res Treat. 2013;137(3):927–37.CrossRefPubMedGoogle Scholar
  14. 14.
    Pinato DJ, Nya P, Sharma R, Mauri FA. CD24: a potential new marker in differentiating malignant mesothelioma from pulmonary adenocarcinoma. J Clin Pathol. 2013;66(3):256–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Li J, Li C, Yuan H, Gong F. Clinical value of CD24 expression in retinoblastoma. J Biomed Biotechnol. 2012;2012:158084.Google Scholar
  16. 16.
    Deng J, Gao G, Wang L, Wang T, Yu J, Zhao Z. CD24 expression as a marker for predicting clinical outcome in human gliomas. J Biomed Biotechnol. 2012;2012:517172.Google Scholar
  17. 17.
    Oksvold MP, Kullmann A, Forfang L, Kierulf B, Li M, Brech A, et al. Expression of B-cell surface antigens in subpopulations of exosomes released from B-cell lymphoma cells. Clin Ther. 2014;36(6):847–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Cherciu I, Bărbălan A, Pirici D, Mărgăritescu C, Săftoiu A. Stem cells, colorectal cancer and cancer stem cell markers correlations. Curr Health Sci J. 2014;40(3):153–61.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Carrasco E, Alvarez PJ, Prados J, Melguizo C, Rama AR, Aránega A, et al. Cancer stem cells and their implication in breast cancer. Eur J Clin Invest. 2014;44(7):678–87.CrossRefPubMedGoogle Scholar
  20. 20.
    Xu L. Cancer stem cell in the progression and therapy of pancreatic cancer. Front Biosci (Landmark Ed). 2013;18:795–802.CrossRefGoogle Scholar
  21. 21.
    Gangopadhyay S, Nandy A, Hor P, Mukhopadhyay A. Breast cancer stem cells: a novel therapeutic target. Clin Breast Cancer. 2013;13(1):7–15.CrossRefPubMedGoogle Scholar
  22. 22.
    Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol. 2012;44(12):2144–51.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Li B, Shao Q, Ji D, Li F, Guo X, Chen G. Combined aberrant expression of N-Myc downstream-regulated gene 2 and CD24 is associated with disease-free survival and overall survival in patients with hepatocellular carcinoma. Diagn Pathol. 2014;9:209.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24 (+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011;9(1):50–63.Google Scholar
  26. 26.
    Chen BD, Hui YF, Zhang HB, Fan LF, Si MH, Yang GS. Expression of CD90/EpCAM/CD24 in hepatocellular carcinoma cell lines at various stages of differentiation. Zhonghua Gan Zang Bing Za Zhi. 2013;21(9):688–91.Google Scholar
  27. 27.
    Yang XR, Xu Y, Yu B, Zhou J, Li JC, Qiu SJ, et al. CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res. 2009;15(17):5518–27.Google Scholar
  28. 28.
    Li D, Zheng L, Jin L, Zhou Y, Li H, Fu J, et al. CD24 polymorphisms affect risk and progression of chronic hepatitis B virus infection. Hepatology. 2009;50:735–42.CrossRefPubMedGoogle Scholar
  29. 29.
    Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H, et al. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res. 2004;566:9–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMedGoogle Scholar
  31. 31.
    Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Mikulits W. Epithelial to mesenchymal transition in hepatocellular carcinoma. Future Oncol. 2009;5(8):1169–79.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lim SO, Kim HS, Quan X, Ahn SM, Kim H, Hsieh D, et al. Notch1 binds and induces degradation of Snail in hepatocellular carcinoma. BMC Biol. 2011;9:83.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sun Q, Wang R, Wang Y, Luo J, Wang P, Cheng B. Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma. Oncol Rep. 2014;31(2):933–9.Google Scholar
  35. 35.
    Wang F, Xia X, Wang J, Sun Q, Luo J, Cheng B. Notch1 signaling contributes to the oncogenic effect of HBx on human hepatic cells. Biotechnol Lett. 2013;35(1):29–37.Google Scholar
  36. 36.
    Zhou L, Wang DS, Li QJ, Sun W, Zhang Y, Dou KF. The down-regulation of Notch1 inhibits the invasion and migration of hepatocellular carcinoma cells by inactivating the cyclooxygenase-2/ Snail/ E-cadherin pathway in vitro. Dig Dis Sci. 2013;58(4):1016–25.Google Scholar
  37. 37.
    Cany J, Tran L, Gauttier V, Judor JP, Vassaux G, Ferry N, et al. Immunotherapy of hepatocellular carcinoma: is there a place for regulatory T-lymphocyte depletion? Immunotherapy. 2011;3(4s):32–4.Google Scholar
  38. 38.
    Efron PA, Tsujimoto H, Bahjat FR, Ungaro R, Debernardis J, Tannahill C, et al. Differential maturation of murine bone-marrow derived dendritic cells with lipopolysaccharide and tumor necrosis factor-alpha. J Endotoxin Res. 2005;11(3):145–60.PubMedGoogle Scholar
  39. 39.
    Yang Y, Hou J, Lin Z, Zhuo H, Chen D, Zhang X, et al. Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells. Cell Mol Immunol. 2014;11(2):184–96.Google Scholar
  40. 40.
    Henniker AJ. CD24. J Biol Regul Homeost Agents. 2001;15:182–4.PubMedGoogle Scholar
  41. 41.
    Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA. Autophagy positively regulates the CD44(+) CD24(−/low) breast cancer stem-like phenotype. Cell Cycle. 2011;10:3871–85.Google Scholar
  42. 42.
    Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res. 2005;65(23):10783–93.Google Scholar
  43. 43.
    Tang MR, Wang YX, Guo S, Han SY, Li HH, Jin SF. CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma. Int J Clin Exp Med. 2014;7(11):4337–41.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kang KS, Choi YP, Gao MQ, Kang S, Kim BG, Lee JH, et al. CD24+ ovary cancer cells exhibit an invasive mesenchymal phenotype. Biochem Biophys Res Commun. 2013;432(2):333–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Huang LR, Hsu HC. Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation. Cancer Res. 1995;55(20):4717–21.PubMedGoogle Scholar
  46. 46.
    Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 2003;63(23):8323–9.PubMedGoogle Scholar
  47. 47.
    Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012;143(6):1660–9.Google Scholar
  48. 48.
    Gao J, Dong Y, Zhang B, Xiong Y, Xu W, Cheng Y, et al. Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells. Int J Oncol. 2012;41(5):1773–81.Google Scholar
  49. 49.
    Zhou L, Zhang N, Li QJ, Sun W, Zhang Y, Wang DS, et al. Associations between high levels of Notch1 expression and high invasion and poor overall survival in hepatocellular carcinoma. Tumour Biol. 2013;34(1):543–53.CrossRefPubMedGoogle Scholar
  50. 50.
    Li Y, Ma J, Qian X, Wu Q, Xia J, Miele L, et al. Regulation of EMT by Notch signaling pathway in tumor progression. Curr Cancer Drug Targets. 2013;13(9):957–62.Google Scholar
  51. 51.
    Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 2013;341(1):41–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Lim J, Lee KM, Shim J, Shin I. CD24 regulates stemness and the epithelial to mesenchymal transition through modulation of Notch1 mRNA stability by p38MAPK. Arch Biochem Biophys. 2014;558:120–6.Google Scholar
  53. 53.
    Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.CrossRefPubMedGoogle Scholar
  54. 54.
    Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328–39.Google Scholar
  55. 55.
    Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2010;52(3):370–9.Google Scholar
  56. 56.
    Flecken T, Spangenberg HC, Thimme R. Immunobiology of hepatocellular carcinoma. Langenbecks Arch Surg. 2012;397(5):673–80.CrossRefPubMedGoogle Scholar
  57. 57.
    Flecken T, Schmidt N, Spangenberg HC, Thimme R. Hepatocellular carcinoma—from immunobiology to immunotherapy. Z Gastroenterol. 2012;50(1):47–56.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xin Wan
    • 1
  • Ci Cheng
    • 1
  • Qing Shao
    • 2
  • Zhe Lin
    • 1
  • Shuai Lu
    • 1
  • Yun Chen
    • 1
  1. 1.Department of ImmunologyNanjing Medical UniversityNanjingChina
  2. 2.Department of OphthalmologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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