Apoptosis

, Volume 19, Issue 4, pp 643–656 | Cite as

CD24 mediates gastric carcinogenesis and promotes gastric cancer progression via STAT3 activation

Original Paper

Abstract

The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.

Keywords

CD24 Early event Gastric carcinogenesis STAT3 

Supplementary material

10495_2013_949_MOESM1_ESM.eps (1 mb)
Supplementary Fig. 1p-STAT3Tyr705 and STAT3 expression in gastric cell lines. The expression of p-STAT3Tyr705 and STAT3 in GES-1 and GC cell lines were examined by western blotting using GAPDH as the loading control (EPS 1.01 Mb)

References

  1. 1.
    Sugimura T, Terada M, Yokota J, Hirohashi S, Wakabayashi K (1992) Multiple genetic alterations in human carcinogenesis. Environ Health Perspect 98:5–12PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Pirruccello SJ, LeBien TW (1986) The human B cell-associated antigen CD24 is a single chain sialoglycoprotein. J Immunol 136:3779–3784PubMedGoogle Scholar
  3. 3.
    Magnaldo T, Barrandon Y (1996) CD24 (heat stable antigen, nectadrin), a novel keratinocyte differentiation marker, is preferentially expressed in areas of the hair follicle containing the colony-forming cells. J Cell Sci 109(Pt 13):3035–3045PubMedGoogle Scholar
  4. 4.
    Suzuki T, Kiyokawa N, Taguchi T, Sekino T, Katagiri YU, Fujimoto J (2001) CD24 induces apoptosis in human B cells via the glycolipid-enriched membrane domains/rafts-mediated signaling system. J Immunol 166:5567–5577PubMedGoogle Scholar
  5. 5.
    Pirruccello SJ, Lang MS (1990) Differential expression of CD24-related epitopes in mycosis fungoides/Sezary syndrome: a potential marker for circulating Sezary cells. Blood 76:2343–2347PubMedGoogle Scholar
  6. 6.
    Raife TJ, Lager DJ, Kemp JD, Dick FR (1994) Expression of CD24 (BA-1) predicts monocytic lineage in acute myeloid leukemia. Am J Clin Pathol 101:296–299PubMedGoogle Scholar
  7. 7.
    Lavabre-Bertrand T, Duperray C, Brunet C, Poncelet P, Exbrayat C, Bourquard P et al (1994) Quantification of CD24 and CD45 antigens in parallel allows a precise determination of B-cell maturation stages: relevance for the study of B-cell neoplasias. Leukemia 8:402–408PubMedGoogle Scholar
  8. 8.
    Lim SC, Oh SH (2005) The role of CD24 in various human epithelial neoplasias. Pathol Res Pract 201:479–486PubMedCrossRefGoogle Scholar
  9. 9.
    Darwish NS, Kim MA, Chang MS, Lee HS, Lee BL, Kim YI et al (2004) Prognostic significance of CD24 expression in gastric carcinoma. Cancer Res Treat 36:298–302PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Takahashi M, Nakajima M, Ogata H, Domeki Y, Ohtsuka K, Ihara K et al (2012) CD24 expression is associated with progression of gastric cancer. Hepatogastroenterology 60:653–658Google Scholar
  11. 11.
    Sagiv E, Starr A, Rozovski U, Khosravi R, Altevogt P, Wang T et al (2008) Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res 68:2803–2812PubMedCrossRefGoogle Scholar
  12. 12.
    Bretz NP, Salnikov AV, Perne C, Keller S, Wang X, Mierke CT et al (2012) CD24 controls Src/STAT3 activity in human tumors. Cell Mol Life Sci 69:3863–3879PubMedCrossRefGoogle Scholar
  13. 13.
    Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO (2011) CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9:50–63PubMedCrossRefGoogle Scholar
  14. 14.
    Xiong H, Su WY, Liang QC, Zhang ZG, Chen HM, Du W et al (2009) Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. Lab Investig 89:717–725PubMedCrossRefGoogle Scholar
  15. 15.
    Wang W, Wang X, Peng L, Deng Q, Liang Y, Qing H et al (2010) CD24-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Cancer Sci 101:112–119PubMedCrossRefGoogle Scholar
  16. 16.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  17. 17.
    Song YX, Yue ZY, Wang ZN, Xu YY, Luo Y, Xu HM et al (2011) MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol Cancer 10:1PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lu R, Wang X, Chen ZF, Sun DF, Tian XQ, Fang JY (2007) Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells. J Biol Chem 282:12249–12259PubMedCrossRefGoogle Scholar
  19. 19.
    Chou YY, Jeng YM, Lee TT, Hu FC, Kao HL, Lin WC et al (2007) Cytoplasmic CD24 expression is a novel prognostic factor in diffuse-type gastric adenocarcinoma. Ann Surg Oncol 14:2748–2758PubMedCrossRefGoogle Scholar
  20. 20.
    Yamaguchi H, Wang HG (2004) CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 279:45495–45502PubMedCrossRefGoogle Scholar
  21. 21.
    Rosati E, Sabatini R, Rampino G, De Falco F, Di Ianni M, Falzetti F et al (2010) Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL. Blood 116:2713–2723PubMedCrossRefGoogle Scholar
  22. 22.
    Yong CS, Ou Yang CM, Chou YH, Liao CS, Lee CW, Lee CC (2012) CD44/CD24 expression in recurrent gastric cancer: a retrospective analysis. BMC Gastroenterol 12:95PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Bektas S, Bahadir B, Ucan BH, Ozdamar SO (2010) CD24 and galectin-1 expressions in gastric adenocarcinoma and clinicopathologic significance. Pathol Oncol Res 16:569–577PubMedCrossRefGoogle Scholar
  24. 24.
    Akashi T, Shirasawa T, Hirokawa K (1994) Gene expression of CD24 core polypeptide molecule in normal rat tissues and human tumor cell lines. Virchows Arch 425:399–406PubMedCrossRefGoogle Scholar
  25. 25.
    Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M et al (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–418PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Shirasawa T, Akashi T, Sakamoto K, Takahashi H, Maruyama N, Hirokawa K (1993) Gene expression of CD24 core peptide molecule in developing brain and developing non-neural tissues. Dev Dyn 198:1–13PubMedCrossRefGoogle Scholar
  27. 27.
    Duckworth CA, Clyde D, Pritchard DM (2012) CD24 is expressed in gastric parietal cells and regulates apoptosis and the response to Helicobacter felis infection in the murine stomach. Am J Physiol Gastrointest Liver Physiol 303:G915–G926PubMedCrossRefGoogle Scholar
  28. 28.
    Kim SS, Ruiz VE, Carroll JD, Moss SF (2011) Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett 305:228–238PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H et al (2009) Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res 69:632–639PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Jackson CB, Judd LM, Menheniott TR, Kronborg I, Dow C, Yeomans ND et al (2007) Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression. J Pathol 213:140–151PubMedCrossRefGoogle Scholar
  31. 31.
    Miller BA, Antognetti G, Springer TA (1985) Identification of cell surface antigens present on murine hematopoietic stem cells. J Immunol 134:3286–3290PubMedGoogle Scholar
  32. 32.
    Chappel MS, Hough MR, Mittel A, Takei F, Kay R, Humphries RK (1996) Cross-linking the murine heat-stable antigen induces apoptosis in B cell precursors and suppresses the anti-CD40-induced proliferation of mature resting B lymphocytes. J Exp Med 184:1639–1649PubMedCrossRefGoogle Scholar
  33. 33.
    Senner V, Sturm A, Baur I, Schrell UH, Distel L, Paulus W (1999) CD24 promotes invasion of glioma cells in vivo. J Neuropathol Exp Neurol 58:795–802PubMedCrossRefGoogle Scholar
  34. 34.
    Kristiansen G, Winzer KJ, Mayordomo E, Bellach J, Schluns K, Denkert C et al (2003) CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res 9:4906–4913PubMedGoogle Scholar
  35. 35.
    Kim HJ, Kim JB, Lee KM, Shin I, Han W, Ko E et al (2007) Isolation of CD24(high) and CD24(low/−) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett 258:98–108PubMedCrossRefGoogle Scholar
  36. 36.
    Sagiv E, Memeo L, Karin A, Kazanov D, Jacob-Hirsch J, Mansukhani M et al (2006) CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis. Gastroenterology 131:630–639PubMedCrossRefGoogle Scholar
  37. 37.
    Pena C, Garcia JM, Larriba MJ, Barderas R, Gomez I, Herrera M et al (2009) SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue. Oncogene 28:4375–4385PubMedCrossRefGoogle Scholar
  38. 38.
    Alvarez-Diaz S, Valle N, Garcia JM, Pena C, Freije JM, Quesada V et al (2009) Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. J Clin Investig 119:2343–2358PubMedCrossRefGoogle Scholar
  39. 39.
    Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25:621–628PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Arias AM (2001) Epithelial mesenchymal interactions in cancer and development. Cell 105:425–431PubMedCrossRefGoogle Scholar
  41. 41.
    Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC et al (2012) Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem 287:5819–5832PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ et al (2008) Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia 10:287–297PubMedCentralPubMedGoogle Scholar
  43. 43.
    Liu CY, Tseng LM, Su JC, Chang KC, Chu PY, Tai WT et al (2013) Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res 15:R63PubMedCrossRefGoogle Scholar
  44. 44.
    Jang J, Jeong SJ, Kwon HY, Jung JH, Sohn EJ, Lee HJ et al (2013) Decursin and doxorubicin are in synergy for the induction of apoptosis via STAT3 and/or mTOR pathways in human multiple myeloma cells. Evid Based Complement Altern Med 2013:506324Google Scholar
  45. 45.
    Jung JH, Jeong SJ, Kim JH, Jung SK, Jung DB, Lee D et al (2013) Inactivation of HDAC3 and STAT3 is critically involved in 1-stearoyl-sn-glycero-3-phosphocholine-induced apoptosis in chronic myelogenous leukemia K562 cells. Cell Biochem Biophys 67:1379–1389Google Scholar
  46. 46.
    Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ (2002) Inhibition of constitutively active STAT3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21:8404–8413PubMedCrossRefGoogle Scholar
  47. 47.
    Choi HJ, Lee JH, Park SY, Cho JH, Han JS (2009) STAT3 is involved in phosphatidic acid-induced Bcl-2 expression in HeLa cells. Exp Mol Med 41:94–101PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Xu W, Chen GS, Shao Y, Li XL, Xu HC, Zhang H et al (2013) Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells. Cancer Lett 332:11–18PubMedCrossRefGoogle Scholar
  49. 49.
    Lin HL, Yang MH, Wu CW, Chen PM, Yang YP, Chu YR et al (2007) 2-Methoxyestradiol attenuates phosphatidylinositol 3-kinase/Akt pathway-mediated metastasis of gastric cancer. Int J Cancer 121:2547–2555PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang X, Yue P, Page BD, Li T, Zhao W, Namanja AT et al (2012) Orally bioavailable small-molecule inhibitor of transcription factor STAT3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci USA 109:9623–9628PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R et al (2009) Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27:1006–1020PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Zhang C, Li C, He F, Cai Y, Yang H (2011) Identification of CD44+CD24+ gastric cancer stem cells. J Cancer Res Clin Oncol 137:1679–1686PubMedCrossRefGoogle Scholar
  53. 53.
    Chen S, Hou JH, Feng XY, Zhang XS, Zhou ZW, Yun JP et al (2013) Clinicopathologic significance of putative stem cell marker, CD44 and CD133, in human gastric carcinoma. J Surg Oncol 107:799–806PubMedCrossRefGoogle Scholar
  54. 54.
    Doventas A, Bilici A, Demirell F, Ersoy G, Turna H, Doventas Y (2012) Prognostic significance of CD44 and c-erb-B2 protein overexpression in patients with gastric cancer. Hepatogastroenterology 59:2196–2201PubMedGoogle Scholar
  55. 55.
    Jang BI, Li Y, Graham DY, Cen P (2011) The role of CD44 in the pathogenesis, diagnosis, and therapy of gastric cancer. Gut Liver 5:397–405PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Dhingra S, Feng W, Brown RE, Zhou Z, Khoury T, Zhang R et al (2011) Clinicopathologic significance of putative stem cell markers, CD44 and nestin, in gastric adenocarcinoma. Int J Clin Exp Pathol 4:733–741PubMedCentralPubMedGoogle Scholar
  57. 57.
    Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K et al (2012) Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int 62:112–119PubMedCrossRefGoogle Scholar
  58. 58.
    Chen W, Zhang X, Chu C, Cheung WL, Ng L, Lam S et al (2013) Identification of CD44+ cancer stem cells in human gastric cancer. Hepatogastroenterology 60:949–954Google Scholar
  59. 59.
    Khurana SS, Riehl TE, Moore BD, Fassan M, Rugge M, Romero-Gallo J et al (2013) The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation. J Biol Chem 288:16085–16097PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.GI DivisionRen Ji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), State Key Laboratory of Oncogene and Related GenesShanghaiChina

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