Tumor Biology

, Volume 36, Issue 4, pp 2785–2792 | Cite as

Association between polymorphisms of microRNA-binding sites in integrin genes and gastric cancer in Chinese Han population

  • Xingbo Song
  • Huiyu Zhong
  • Juan Zhou
  • Xuejiao Hu
  • Yi Zhou
  • Yuanxin Ye
  • Xiaojun Lu
  • Jun Wang
  • Binwu Ying
  • Lanlan Wang
Research Article

Abstract

Highly elevated expression of integrin has been observed in a variety of malignant tumors. Single nucleotide polymorphisms (SNPs) in the microRNA-binding sites in the 3′ UTR region of target genes may result in the level change of target gene expression and subsequently susceptible to diseases, including cancer. In this study, we aimed to investigate the association between polymorphisms of microRNA-binding sites of integrin genes and gastric cancer (GC) in Chinese Han population. Five SNPs of the microRNA-binding sites in the 3′ UTR region of integrin genes (rs1062484 C/T in ITGA3, rs17664 A/G in ITGA6, rs3809865 A/T in ITGB3, rs743554 C/T in ITGB4, and rs2675 A/C in ITGB5) were studied using high resolution melting (HRM) analysis in 1000 GC patients and 1000 unrelated controls. The polymorphism of SNP rs2675 was associated with susceptibility of GC [odds ratio (OR) = 0.52, 95 % confidence interval (CI) = 0.28–0.97, P = 0.028]. In addition, genotype AA of rs2675 and genotype GG of rs17664 were associated with a lower chance of GC at stage 1b [OR = 0.39 (0.18–0.85), P = 0.009; and OR = 0.37 (0.17–0.78), P = 0.004, respectively]; also, the frequency of allele G of rs17664 was associated with a lower chance of stage 1b tumor [OR = 0.50 (0.26–0.95), P = 0.021]. Furthermore, the frequency of genotype AA and allele A of rs3809865 were associated with a higher risk of stage 4 GC [OR = 1.85 (1.11–3.09), P = 0.012; and OR = 1.52 (0.99–2.33), P = 0.043, respectively]. For rs17664, GG genotype and allele G appeared to be associated with a higher risk with GC with lymphatic metastasis 3b [OR = 1.76 (1.00–3.11), P = 0.036; and OR = 1.64 (0.98–2.75), P = 0.048, respectively]. Our data suggest that polymorphisms of the microRNA-binding sites in the 3′ UTR region of integrin are associated with GC susceptibility (rs2675), tumor stage (rs2675, rs17664, and rs3809865), and lymphatic metastasis (rs17664) in Chinese Han population.

Keywords

MicroRNA Single nucleotide polymorphism Integrin Gastric cancer 

Notes

Acknowledgments

We gratefully acknowledge all the staff who participated in this study. This work was supported by grants from National Natural Science Foundation of China (No. 81101326). We thank Drs. Junping Xin and Haiyan Chen (Loyola University Medical Center) for critical review and editorial assistance during manuscript preparation.

Conflict of interest

The authors declare that they have no conflict of interest.

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.
    Coupland VH, Lagergren J, Lüchtenborg M, Jack RH, Allum W, Holmberg L, et al. Hospital volume, proportion resected and mortality from oesophageal and gastric cancer: a population-based study in England, 2004–2008. Gut. 2013;62:961–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Guggenheim DE, Shah MA. Gastric cancer epidemiology and risk factors. J Surg Oncol. 2013;107:230–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010;17:3077–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, et al. Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 2004;315:686–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Stadtländer CT, Waterbor JW. Molecular epidemiology, pathogenesis and prevention of gastric cancer. Carcinogenesis. 1999;20:2195–208.CrossRefPubMedGoogle Scholar
  7. 7.
    Rocco A, Nardone G. Diet, H pylori infection and gastric cancer: evidence and controversies. World J Gastroenterol. 2007;13:2901–12.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta. 2013;424:53–65.CrossRefPubMedGoogle Scholar
  9. 9.
    Lu F, Xue JX, Hu YC, Gan L, Shi Y, Yang HS, et al. CARP is a potential tumor suppressor in gastric carcinoma and a single-nucleotide polymorphism in CARP genemight increase the risk of gastric carcinoma. PLoS One. 2014;9:e97743.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wang M, Li C, Nie H, Lv X, Qu Y, Yu B, et al. Down-regulated miR-625 suppresses invasion and metastasis of gastric cancer by targeting ILK. FEBS Lett. 2012;586:2382–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Palmero EI, de Campos SG, Campos M, de Souza NC, Guerreiro ID, Carvalho AL, et al. Mechanisms and role of microRNA deregulation in cancer onset and progression. Genet Mol Biol. 2011;34:363–70.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Kent OA, Mendell JT. A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene. 2006;25:6188–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med. 2014;20:360–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.CrossRefPubMedGoogle Scholar
  16. 16.
    Tanentzapf G, Brown NH. An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton. Nat Cell Biol. 2006;8:601–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Bökel C, Brown NH. Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell. 2002;3:311–21.CrossRefPubMedGoogle Scholar
  18. 18.
    Ye P, Li Z, Jiang H, Liu T. SNPs in microRNA-binding sites in the ITGB1 and ITGB3 3′ UTR increase colorectal cancer risk. Cell Biochem Biophys. 2014;70:601–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Liu J, Huang J, He Y, Liu J, Liao B, Liao G. Genetic variants in the integrin gene predicted microRNA-binding sites were associated with the risk of prostate cancer. Mol Carcinog. 2014;53:280–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Brendle A, Lei H, Brandt A, Johansson R, Enquist K, Henriksson R, et al. Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis. 2008;29:1394–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Chen J, Liu NN, Li JQ, Yang L, Zeng Y, Zhao XM, et al. Association between ITGA2 C807T polymorphism and gastric cancer risk. World J Gastroenterol. 2011;17:2860–6.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Scartozzi M, Loretelli C, Bearzi I, Mandolesi A, Galizia E, Onofri A, et al. Allele polymorphisms of tumor integrins correlate with peritoneal carcinosis capability of gastric cancer cells in radically resected patients. Ann Oncol. 2011;22:897–902.CrossRefPubMedGoogle Scholar
  23. 23.
    Farazi TA, Spitzer JI, Morozov P, Tuschl T. miRNAs in human cancer. J Pathol. 2011;223:102–15.CrossRefPubMedGoogle Scholar
  24. 24.
    Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K, et al. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol. 2010;12:372–9.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Segura MF, Belitskaya-Lévy I, Rose AE, Zakrzewski J, Gaziel A, Hanniford D, et al. Melanoma microRNA signature predicts post-recurrence survival. Clin Cancer Res. 2010;16:1577–86.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ahn DH, Rah H, Choi YK, Jeon YJ, Min KT, Kwack K, et al. Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the Korean population. Mol Carcinog. 2013;52:39–51.CrossRefGoogle Scholar
  27. 27.
    Georges M, Coppieters W, Charlie C. Polymorphic miRNA-mediated gene regulation: contribution to phenotypic variation and disease. Curr Opin Genet Dev. 2007;17:166–76.CrossRefPubMedGoogle Scholar
  28. 28.
    Liang D, Meyer L, Chang DW, Lin J, Pu X, Ye Y, et al. Genetic variants in microRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. Cancer Res. 2010;70:9765–76.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M, et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res. 2010;70:2789–98.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wynendaele J, Böhnke A, Leucci E, Nielsen SJ, Lambertz I, Hammer S, et al. An illegitimate microRNA target site within the 3′ UTR of MDM4 affects ovarian cancer progression and chemosensitivity. Cancer Res. 2010;70:9641–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Xu Y, Ma H, Yu H, Liu Z, Wang LE, Tan D, et al. The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer. PLoS ONE. 2013;8:e64973.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Paszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK, Godula K, et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature. 2014;511:319–25.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dutta A, Li J, Lu H, Akech J, Pratap J, Wang T, et al. Integrin αvβ6 promotes an osteolytic program in cancer cells by upregulating MMP2. Cancer Res. 2014;74:1598–608.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lee C, Lee C, Lee S, Siu A, Ramos DM. The cytoplasmic extension of the integrin β6 subunit regulates epithelial-to-mesenchymal transition. Anticancer Res. 2014;34:659–64.PubMedGoogle Scholar
  35. 35.
    Pocheć E, Janik M, Hoja-Łukowicz D, Link-Lenczowski P, Przybyło M, Lityńska A. Expression of integrins α3β1 and α5β1 and GIcNAc β1,6 glycan branching influences metastatic melanoma cell migration on fibronectin. Eur J Cell Biol. 2013;92:355–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Saito Y, Sekine W, Sano R, Komatsu S, Mizuno H, Katabami K, et al. Potentiation of cell invasion and matrix metalloproteinase production by alpha3beta1 integrin-mediated adhesion of gastric carcinoma cells to laminin-5. Clin Exp Metastasis. 2010;27:197–205.CrossRefPubMedGoogle Scholar
  37. 37.
    Pawelek JM, Chakraborty AK. The cancer cell–leukocyte fusion theory of metastasis. Adv Cancer Res. 2008;101:397–444.CrossRefPubMedGoogle Scholar
  38. 38.
    Chen W, Harbeck MC, Zhang W, Jacobson JR. MicroRNA regulation of integrins. Transl Res. 2013;162:133–43.CrossRefPubMedGoogle Scholar
  39. 39.
    Wang Y, Long L, Li T, Zhou Y, Jiang L, Zeng X, et al. Polymorphisms of microRNA-binding sites in integrin genes are associated with oral squamous cell carcinoma susceptibility and progression. Tohoku J Exp Med. 2014;233:33–41.CrossRefPubMedGoogle Scholar
  40. 40.
    Ma XR, Cheng H, Wang XY, Liu H, Zhao D. Single-nucleotide polymorphisms of integrins are associated with the risk and lymph node metastasis of oral squamous cell carcinoma. Med Oncol. 2012;29:2492–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang Y, Han Y, Dong L, Yu H, Cheng L, Zhao X, et al. Genetic variation of ITGB3 is associated with asthma in Chinese Han children. PLoS One. 2013;8:e56914.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ma DQ, Rabionet R, Konidari I, Jaworski J, Cukier HN, Wright HH, et al. Association and gene-gene interaction of SLC6A4 and ITGB3 in autism. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:477–83.PubMedGoogle Scholar
  43. 43.
    Azimzadeh P, Romani S, Mohebbi SR, Mahmoudi T, Vahedi M, Fatemi SR, et al. Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. Cancer Genet. 2012;205:501–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Li ZH, Pan XM, Han BW, Guo XM, Zhang Z, Jia J, et al. A let-7 binding site polymorphism rs712 in the KRAS 3′ UTR is associated with an increased risk of gastric cancer. Tumour Biol. 2013;34:3159–63.CrossRefPubMedGoogle Scholar
  45. 45.
    Lin Y, Nie Y, Zhao J, Chen X, Ye M, Li Y, et al. Genetic polymorphism at miR-181a binding site contributes to gastric cancer susceptibility. Carcinogenesis. 2012;33:2377–83.CrossRefPubMedGoogle Scholar
  46. 46.
    Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2:91–100.CrossRefPubMedGoogle Scholar
  47. 47.
    Kumar CC. Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets. 2003;4:123–31.CrossRefPubMedGoogle Scholar
  48. 48.
    Lamb LE, Zarif JC, Miranti CK. The androgen receptor induces integrin α6β1 to promote prostate tumor cell survival via NF-κB and Bcl-xL independently of PI3K signaling. Cancer Res. 2011;71:2739–49.CrossRefPubMedGoogle Scholar
  49. 49.
    Cordes N, Park CC. beta1 integrin as a molecular therapeutic target. Int J Radiat Biol. 2007;83:753–60.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xingbo Song
    • 1
  • Huiyu Zhong
    • 1
  • Juan Zhou
    • 1
  • Xuejiao Hu
    • 1
  • Yi Zhou
    • 1
  • Yuanxin Ye
    • 1
  • Xiaojun Lu
    • 1
  • Jun Wang
    • 1
  • Binwu Ying
    • 1
  • Lanlan Wang
    • 1
  1. 1.Department of Laboratory Medicine, West China HospitalSichuan UniversityChengduChina

Personalised recommendations