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Tumor Biology

, Volume 37, Issue 5, pp 6971–6977 | Cite as

Effect of CD44 gene polymorphisms on risk of transitional cell carcinoma of the urinary bladder in Taiwan

  • Wei-Chun Weng
  • Yu-Hui Huang
  • Shun-Fa Yang
  • Shian-Shiang Wang
  • Wu-Hsien Kuo
  • Chao-Wen Hsueh
  • Ching-Hsuan Huang
  • Ying-Erh Chou
Original Article

Abstract

The carcinogenesis of transitional cell carcinoma (TCC) of the urinary bladder involves etiological factors, such as ethnicity, the environment, genetics, and diet. Cluster of differentiation (CD44), a well-known tumor marker, plays a crucial role in regulating tumor cell differentiation and metastasis. This study investigated the effect of CD44 single nucleotide polymorphisms (SNPs) on TCC risk and clinicopathological characteristics. Five SNPs of CD44 were analyzed through real-time polymerase chain reaction in 275 patients with TCC and 275 participants without cancer. In this study, we observed that CD44 rs187115 polymorphism carriers with the genotype of at least one G were associated with TCC risk. Furthermore, TCC patients who carried at least one G allele at CD44 rs187115 had a higher stage risk than did patients carrying the wild-type allele (p < 0.05). In addition, The AATAC or GACGC haplotype among the five CD44 sites was also associated with a reduced risk of TCC. In conclusion, our results suggest that CD44 SNPs influence the risk of TCC. Patients with CD44 rs187115 variant genotypes (AG + GG) exhibited a higher risk of TCC; these patients may possess chemoresistance to developing late-stage TCC compared with those with the wild-type genotype. The CD44 rs187115 SNP may predict poor prognosis in patients with TCC.

Keywords

Single nucleotide polymorphism CD44 Transitional cell carcinoma 

Notes

Acknowledgments

This study was supported by a research grant from Chung Shan Medical University and Tungs’ Taichung Metro Harbor Hospital (CSMU-TTM-103-01).

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Tung MC, Hsieh MJ, Wang SS, Yang SF, Chen SS, Wang SW, et al. Associations of VEGF-C genetic polymorphisms with urothelial cell carcinoma susceptibility differ between smokers and non-smokers in Taiwan. PLoS One. 2014;9:e91147.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bid HK, Manchanda PK, Mittal RD. Association of interleukin-1Ra gene polymorphism in patients with bladder cancer: case control study from north India. Urology. 2006;67:1099–104.CrossRefPubMedGoogle Scholar
  4. 4.
    Baris D, Karagas MR, Verrill C, Johnson A, Andrew AS, Marsit CJ, et al. A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101:1553–61.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kellen E, Zeegers M, Paulussen A, Vlietinck R, Vlem EV, Veulemans H, et al. Does occupational exposure to pahs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; The belgian case control study on bladder cancer risk. Cancer Lett. 2007;245:51–60.Google Scholar
  6. 6.
    Williams SG, Stein JP. Molecular pathways in bladder cancer. Urol Res. 2004;32:373–85.CrossRefPubMedGoogle Scholar
  7. 7.
    Pow-Sang JM, Seigne JD. Contemporary management of superficial bladder cancer. Cancer Control: J Moffitt Cancer Cent. 2000;7:335–9.Google Scholar
  8. 8.
    Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol: Off J Am Soc Clin Oncol. 2001;19:666–75.CrossRefGoogle Scholar
  9. 9.
    Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Mol Pathol: MP. 1999;52:189–96.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4:33–45.CrossRefPubMedGoogle Scholar
  11. 11.
    Zoller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011;11:254–67.CrossRefPubMedGoogle Scholar
  12. 12.
    Marhaba R, Zoller M. CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol. 2004;35:211–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Hill A, McFarlane S, Johnston PG, Waugh DJ. The emerging role of CD44 in regulating skeletal micrometastasis. Cancer Lett. 2006;237:1–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Marhaba R, Klingbeil P, Nuebel T, Nazarenko I, Buechler MW, Zoeller M. CD44 and EpCAM: cancer-initiating cell markers. Curr Mol Med. 2008;8:784–804.CrossRefPubMedGoogle Scholar
  15. 15.
    Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104:973–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang SJ, Bourguignon LY. Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. Am J Pathol. 2011;178:956–63.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Southgate J, Trejdosiewicz LK, Smith B, Selby PJ. Patterns of splice variant CD44 expression by normal human urothelium in situ and in vitro and by bladder-carcinoma cell lines. Int J Cancer. 1995;62:449–56.CrossRefPubMedGoogle Scholar
  19. 19.
    Ioachim E, Charchanti A, Stavropoulos N, Athanassiou E, Bafa M, Agnantis NJ. Expression of cathepsin D in urothelial carcinoma of the urinary bladder: an immunohistochemical study including correlations with extracellular matrix components, CD44, p53, Rb, c-erbB-2 and the proliferation indices. Anticancer Res. 2002;22:3383–8.PubMedGoogle Scholar
  20. 20.
    Chien MH, Yang JS, Chu YH, Lin CH, Wei LH, Yang SF, et al. Impacts of CA9 gene polymorphisms and environmental factors on oral-cancer susceptibility and clinicopathologic characteristics in Taiwan. PLoS One. 2012;7:e51051.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, et al. Genetic analysis of genome-wide variation in human gene expression. Nature. 2004;430:743–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 2007;67:9609–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Chou YE, Hsieh MJ, Chiou HL, Lee HL, Yang SF, Chen TY. CD44 gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features. BioMed Res Int. 2014;2014:231474.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Chou YE, Hsieh MJ, Hsin CH, Chiang WL, Lai YC, Lee YH, et al. CD44 gene polymorphisms and environmental factors on oral cancer susceptibility in taiwan. PLoS One. 2014;9:e93692.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gerger A, Zhang W, Yang D, Bohanes P, Ning Y, Winder T, et al. Common cancer stem cell gene variants predict colon cancer recurrence. Clin Cancer Res: Off J Am Assoc Cancer Res. 2011;17:6934–43.CrossRefGoogle Scholar
  26. 26.
    Jiang L, Deng J, Zhu X, Zheng J, You Y, Li N, et al. CD44 rs13347 C > T polymorphism predicts breast cancer risk and prognosis in Chinese populations. Breast Cancer Research: BCR. 2012;14:R105.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Vazquez A, Grochola LF, Bond EE, Levine AJ, Taubert H, Muller TH, et al. Chemosensitivity profiles identify polymorphisms in the p53 network genes 14-3-3tau and CD44 that affect sarcoma incidence and survival. Cancer Res. 2010;70:172–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Winder T, Ning Y, Yang D, Zhang W, Power DG, Bohanes P, et al. Germline polymorphisms in genes involved in the CD44 signaling pathway are associated with clinical outcome in localized gastric adenocarcinoma. Int J Cancer J Int Cancer. 2011;129:1096–104.CrossRefGoogle Scholar
  29. 29.
    Zhou J, Nagarkatti PS, Zhong Y, Creek K, Zhang J, Nagarkatti M. Unique SNP in CD44 intron 1 and its role in breast cancer development. Anticancer Res. 2010;30:1263–72.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sharma KL, Yadav A, Gupta A, Tulsayan S, Kumar V, Misra S, et al. Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35:2583–9.CrossRefGoogle Scholar
  31. 31.
    Su SC, Hsieh MJ, Chou YE, Fan WL, Yeh CB, Yang SF. Effects of rage gene polymorphisms on the risk and progression of hepatocellular carcinoma. Medicine. 2015;94:e1396.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet. 2005;76:449–62.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hong RL, Pu YS, Chu JS, Lee WJ, Chen YC, Wu CW. Correlation of expression of CD44 isoforms and E-cadherin with differentiation in human urothelial cell lines and transitional cell carcinoma. Cancer Lett. 1995;89:81–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Muller M, Heicappell R, Habermann F, Kaufmann M, Steiner U, Miller K. Expression of CD44v2 in transitional cell carcinoma of the urinary bladder and in urine. Urol Res. 1997;25:187–92.CrossRefPubMedGoogle Scholar
  35. 35.
    Uzgare AR, Xu Y, Isaacs JT. In vitro culturing and characteristics of transit amplifying epithelial cells from human prostate tissue. J Cell Biochem. 2004;91:196–205.CrossRefPubMedGoogle Scholar
  36. 36.
    Li Y, Liu W, Hayward SW, Cunha GR, Baskin LS. Plasticity of the urothelial phenotype: effects of gastro-intestinal mesenchyme/stroma and implications for urinary tract reconstruction. Differ Res Biol Divers. 2000;66:126–35.CrossRefGoogle Scholar
  37. 37.
    Lipponen P, Aaltoma S, Kosma VM, Ala-Opas M, Eskelinen M. Expression of CD44 standard and variant-v6 proteins in transitional cell bladder tumours and their relation to prognosis during a long-term follow-up. J Pathol. 1998;186:157–64.CrossRefPubMedGoogle Scholar
  38. 38.
    Toma V, Hauri D, Schmid U, Ackermann D, Maurer R, Alund G, et al. Focal loss of CD44 variant protein expression is related to recurrence in superficial bladder carcinoma. Am J Pathol. 1999;155:1427–32.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hong RL, Pu YS, Hsieh TS, Chu JS, Lee WJ. Expressions of E-cadherin and exon v6-containing isoforms of CD44 and their prognostic values in human transitional cell carcinoma. J Urol. 1995;153:2025–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest. 2011;121:1064–74.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kuniyasu H, Oue N, Tsutsumi M, Tahara E, Yasui W. Heparan sulfate enhances invasion by human colon carcinoma cell lines through expression of CD44 variant exon 3. Clin Cancer Res: Off J Am Assoc Cancer Res. 2001;7:4067–72.Google Scholar
  42. 42.
    Miyoshi T, Kondo K, Hino N, Uyama T, Monden Y. The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 1997;3:1289–97.Google Scholar
  43. 43.
    Suenaga M, Yamada S, Fuchs BC, Fujii T, Kanda M, Tanaka C, et al. CD44 single nucleotide polymorphism and isoform switching may predict gastric cancer recurrence. J Surg Oncol. 2015;112:622–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Aaltomaa S, Lipponen P, Ala-Opas M, Kosma VM. Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer. Eur Urol. 2001;39:138–44.CrossRefPubMedGoogle Scholar
  45. 45.
    Di Cello F, Flowers VL, Li H, Vecchio-Pagan B, Gordon B, Harbom K, et al. Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells. Mol Cancer. 2013;12:90.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kokko LL, Hurme S, Maula SM, Alanen K, Grenman R, Kinnunen I, et al. Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinoma. Oral Oncol. 2011;47:510–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Liu Y, Qing H, Su X, Wang C, Li Z, Liu S. Association of CD44 gene polymorphism with survival of NSCLC and risk of bone metastasis. Med Sci Monit: Int Med J Exp Clin Res. 2015;21:2694–700.CrossRefGoogle Scholar
  48. 48.
    Esrig D, Spruck 3rd CH, Nichols PW, Chaiwun B, Steven K, Groshen S, et al. P53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol. 1993;143:1389–97.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Orntoft TF, Wolf H. Molecular alterations in bladder cancer. Urol Res. 1998;26:223–33.CrossRefPubMedGoogle Scholar
  50. 50.
    Vet JA, Bringuier PP, Poddighe PJ, Karthaus HF, Debruyne FM, Schalken JA. P53 mutations have no additional prognostic value over stage in bladder cancer. Br J Cancer. 1994;70:496–500.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kuncova J, Kostrouch Z, Viale M, Revoltella R, Mandys V. Expression of CD44v6 correlates with cell proliferation and cellular atypia in urothelial carcinoma cell lines 5637 and HT1197. Folia Biol. 2005;51:3–11.Google Scholar
  52. 52.
    Kuncova J, Urban M, Mandys V. Expression of CD44s and CD44v6 in transitional cell carcinomas of the urinary bladder: comparison with tumour grade, proliferative activity and p53 immunoreactivity of tumour cells. APMIS. 2007;115:1194–205.CrossRefPubMedGoogle Scholar
  53. 53.
    Hofmann M, Rudy W, Gunthert U, Zimmer SG, Zawadzki V, Zoller M, et al. A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. Cancer Res. 1993;53:1516–21.PubMedGoogle Scholar
  54. 54.
    Weg-Remers S, Ponta H, Herrlich P, Konig H. Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J. 2001;20:4194–203.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Reisman DN, Strobeck MW, Betz BL, Sciariotta J, Funkhouser Jr W, Murchardt C, et al. Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. Oncogene. 2002;21:1196–207.CrossRefPubMedGoogle Scholar
  56. 56.
    Strobeck MW, DeCristofaro MF, Banine F, Weissman BE, Sherman LS, Knudsen ES. The BRG-1 subunit of the SWI/SNF complex regulates CD44 expression. J Biol Chem. 2001;276:9273–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Wei-Chun Weng
    • 1
    • 2
  • Yu-Hui Huang
    • 3
    • 4
  • Shun-Fa Yang
    • 1
    • 5
  • Shian-Shiang Wang
    • 1
    • 6
  • Wu-Hsien Kuo
    • 7
  • Chao-Wen Hsueh
    • 7
  • Ching-Hsuan Huang
    • 8
  • Ying-Erh Chou
    • 3
    • 5
  1. 1.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  2. 2.Division of Urology, Department of SurgeryTungs’ Taichung MetroHarbor HospitalTaichungTaiwan
  3. 3.School of MedicineChung Shan Medical UniversityTaichungTaiwan
  4. 4.Department of Physical Medicine and RehabilitationChung Shan Medical University HospitalTaichungTaiwan
  5. 5.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
  6. 6.Division of Urology, Department of SurgeryTaichung Veterans General HospitalTaichungTaiwan
  7. 7.Department of Internal MedicineKaohsiung Armed Forces General HospitalKaohsiungTaiwan
  8. 8.Department of AcupunctureChina Medical University HospitalTaichungTaiwan

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