Virologica Sinica

, Volume 31, Issue 4, pp 306–313 | Cite as

Association of single nucleotide polymorphism rs2065955 of the filaggrin gene with susceptibility to Epstein-Barr virus-associated gastric carcinoma and EBV-negative gastric carcinoma

  • Xiaojing Kuang
  • Lingling Sun
  • Shuzhen Liu
  • Zhenzhen Zhao
  • Danrui Zhao
  • Song Liu
  • Bing Luo
Research Article


The relationship between the Filaggrin gene (FLG) rs2065955 polymorphism and susceptibility to Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) was investigated in Shandong Province, China. We detected the FLG rs2065955 genotype and allele distribution by using PCR and restriction fragment length polymorphism (RFLP) in 64 EBVaGC, 82 EBVnGC, and 111 normal control samples. Immunohistochemistry was used to detect the level of FLG protein in 35 EBVaGC and 51 EBVnGC tumor tissues. Compared with normal controls, the genotype CC and allele C of FLG rs2065955 showed higher frequency in EBVaGC and EBVnGC. There was no significant difference between EBVaGC and EBVnGC in allele distribution of FLG rs2065955, but the genotype CC was found more frequently in EBVaGC than in EBVnGC. The risk of developing either EBVaGC or EBVnGC in genotype CC was higher than in other genotypes. Furthermore, genotype CC of FLG rs2065955 may contribute more to the risk of developing EBVaGC than EBVnGC. There was no significant difference in the expression level of FLG protein between EBVaGC and EBVnGC. In conclusion, the FLG rs2065955 polymorphism was significantly related to gastric carcinoma. Allele C of FLG rs2065955 could be a risk factor for EBVaGC or EBVnGC, while genotype CC of FLG rs2065955 was especially associated with EBVaGC.


Filaggrin gene (FLG) rs2065955 gastric carcinoma Epstein-Barr virus (EBV) gene polymorphism immunohistochemistry 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

12250_2016_3721_MOESM1_ESM.pdf (147 kb)
Supplementary material, approximately 148 KB.
12250_2016_3721_MOESM2_ESM.xls (320 kb)
Supplementary material, approximately 320 KB.
12250_2016_3721_MOESM3_ESM.xlsx (18 kb)
Supplementary material, approximately 20 KB.


  1. Andal N, Shanthi P, Krishnan KB, and Taralaxmi V. 2003. The epstein barr virus and gastric carcinoma. Indian J Pathol Microbiol, 46: 34–36.PubMedGoogle Scholar
  2. Artero-Castro A, Castellvi J, García A, Hernández J, Ramón y Cajal S, Lleonart ME. 2011. Expression of the ribosomal proteins Rplp0, Rplp1, and Rplp2 in gynecologic tumors. Hum Pathol, 42: 194–203.CrossRefPubMedGoogle Scholar
  3. Ashkenazi S, Ortenberg R, Besser M, Schachter J, Markel G. 2016. SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells. Oncotarget. doi: 10.18632/oncotarget.7379.Google Scholar
  4. Bager P, Wohlfahrt J, Sørensen E, Ullum H, Høgdall C K, Palle C, Husemoen LL, Linneberg A, Kjaer SK, Melbye M, and Thyssen JP. 2015. Common filaggrin gene mutations and risk of cervical cancer. Acta Oncol, 54: 217–223.CrossRefPubMedGoogle Scholar
  5. Bowers AJ, Boylan JF. 2004. Nek8, a NIMA family kinase member, is overexpressed in primary human breast tumors. Gene, 328: 135–142.CrossRefPubMedGoogle Scholar
  6. Candi E, Schmidt R, and Melino G. 2005. The cornified envelope: A model of cell death in the skin. Nat Rev Mol Cell Biol, 6: 328–340.CrossRefPubMedGoogle Scholar
  7. Chang EY, Chang YC, Shun CT, Tien YW, Tsai SH, Hee SW, Chen IJ, Chuang LM. 2016. Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2. PLoS One, 11: e0147390.Google Scholar
  8. Chang H, Jeung HC, Jung JJ, Kim TS, Rha SY, Chung HC. 2011. Identification of genes associated with chemosensitivity to SAHA/taxane combination treatment in taxane-resistant breast cancer cells. Breast Cancer Res Treat. 125: 55–63.CrossRefPubMedGoogle Scholar
  9. Chen H, Ma J, Sunkel B, Luo A, Ding F, Li Y, He H, Zhang S, Xu C, Jin Q, Wang Q, and Liu Z. 2013. S100a14: Novel modulator of terminal differentiation in esophageal cancer. Mol Cancer Res, 11: 1542–1553.CrossRefPubMedGoogle Scholar
  10. Cintorino M, Syrjanen S, Leoncini P, Bellizzi de Marco E, Petracca R, Pallini V, Tosi P, Mantyjarvi R, and Syrjanen K. 1988. Altered expression of filaggrin in human papillomavirus (HPV) lesions of the uterine cervix. Arch Gynecol Obstet, 241: 235–247.CrossRefPubMedGoogle Scholar
  11. Cooper CD, Liggins AP, Ait-Tahar K, Roncador G, Banham AH, Pulford K. 2006. PASD1, a DLBCL-associated cancer testis antigen and candidate for lymphoma immunotherapy. Leukemia, 20: 2172–2174.CrossRefPubMedGoogle Scholar
  12. de Benedetto A, Qualia CM, Baroody FM, and Beck LA. 2008. Filaggrin expression in oral, nasal, and esophageal mucosa. J Invest Dermatol, 128: 1594–1597.CrossRefPubMedGoogle Scholar
  13. Fleming JM, Ginsburg E, Oliver SD, Goldsmith P, Vonderhaar BK. 2012. Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer. BMC Cancer, 12: 266.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Fukayama M, Hayashi Y, Iwasaki Y, Chong J, Ooba T, Takizawa T, Koike M, Mizutani S, Miyaki M, and Hirai K. 1994. Epsteinbarr virus-associated gastric carcinoma and epstein-barr virus infection of the stomach. Lab Invest, 71: 73–81.PubMedGoogle Scholar
  15. Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E, Hold G, Tijerina-Menchaca R, Maldonado-Garza HJ, and Perez-Perez GI. 2005. Role of the polymorphic il-1b, il-1rn and tnf-a genes in distal gastric cancer in mexico. Int J Cancer, 114: 237–241.CrossRefPubMedGoogle Scholar
  16. Irvine AD, McLean WH, and Leung DY. 2011. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med, 365: 1315–1327.CrossRefPubMedGoogle Scholar
  17. Khan G, Coates PJ, Gupta RK, Kangro HO, and Slavin G. 1992. Presence of epstein-barr virus in hodgkin’s disease is not exclusive to reed-sternberg cells. Am J Pathol, 140: 757–762.PubMedPubMedCentralGoogle Scholar
  18. Kim Y, Choi JW, Lee JH, Kim YS. 2014. Loss of CDC14B expression in clear cell renal cell carcinoma: meta-analysis of microarray data sets. Am J Clin Pathol, 141: 551–558.CrossRefPubMedGoogle Scholar
  19. Lara C, Serra V, Marzo C, Valcuende F, Castells A, and Bonilla-Musoles F M. 1994. Immunohistochemical localization of filaggrin in benign, premalignant and malignant cervical tissue. Arch Gynecol Obstet, 255: 73–79.CrossRefPubMedGoogle Scholar
  20. Lee MA, Hong YS, Kang JH, Lee KS, You JY, Lee KY, and Park CH. 2004. Detection of epstein-barr virus by pcr and expression of lmp1, p53, cd44 in gastric cancer. Korean J Intern Med, 19: 43–47.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lian YF, Yuan J, Cui Q, Feng QS, Xu M, Bei JX, Zeng YX, Feng L. 2016. Upregulation of KLHDC4 predicts a poor prognosis in human nasopharyngeal carcinoma. PLoS One, 11: e0152820.Google Scholar
  22. Ling XH, Chen ZY, Luo HW, Liu ZZ, Liang YK, Chen GX, Jiang FN, Zhong WD. 2016. BCL9, a coactivator for Wnt/ß- catenin transcription, is targeted by miR-30c and is associated with prostate cancer progression. Oncol Lett. Mar, 11: 2001–2008.Google Scholar
  23. McGlennen RC, Ostrow RS, Carson LF, Stanley MS, and Faras AJ. 1991. Expression of cytokine receptors and markers of differentiation in human papillomavirus-infected cervical tissues. Am J Obstet Gynecol, 165: 696–705.CrossRefPubMedGoogle Scholar
  24. Nagini S. 2012. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol, 4: 156–169.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee S P, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, Di-Giovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, and McLean WH. 2006. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet, 38: 441–446.CrossRefPubMedGoogle Scholar
  26. Partida-Rodriguez O, Torres J, Flores-Luna L, Camorlinga M, Nieves-Ramirez M, Lazcano E, and Perez-Rodriguez M. 2010. Polymorphisms in tnf and hsp-70 show a significant association with gastric cancer and duodenal ulcer. Int J Cancer, 126: 1861–1868.PubMedGoogle Scholar
  27. Rad R, Ballhorn W, Voland P, Eisenacher K, Mages J, Rad L, Ferstl R, Lang R, Wagner H, Schmid RM, Bauer S, Prinz C, Kirschning CJ, and Krug A. 2009. Extracellular and intracellular pattern recognition receptors cooperate in the recognition of helicobacter pylori. Gastroenterology, 136: 2247–2257.CrossRefPubMedGoogle Scholar
  28. Rak R, Haklai R, Elad-Tzfadia G, Wolfson HJ, Carmeli S, Kloog Y. 2014. Novel LIMK2 Inhibitor Blocks Panc-1 Tumor Growth in a mouse xenograft model. Oncoscience, 1: 39–48.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rangel MM, Chaible LM, Nagamine MK, Mennecier G, Cogliati B, de Oliveira KD, Fukumasu H, Sinhorini IL, Mir LM, Dagli ML. 2015. Electroporation transiently decreases GJB2 (connex-in 26) expression in B16/BL6 melanoma cell line. J Membr Biol, 248: 47–52.CrossRefPubMedGoogle Scholar
  30. Roh SA, Park IJ, Yoon YS, Kwon YH, Chung JH, Kim TW, Cho DH, Lim BH, Kim SK, Kim SY, Kim YS, Kim JC. 2016. Feasibility of novel PPP1R15A and proposed ANXA11 single nucleotide polymorphisms as predictive markers for bevacizumab regimen in metastatic colorectal cancer. J Cancer Res Clin Oncol, 142: 1705–1714.CrossRefPubMedGoogle Scholar
  31. Skaaby T, Husemoen LL, Jorgensen T, Johansen JD, Menne T, Szecsi PB, Stender S, Bager P, Thyssen JP, and Linneberg A. 2014. Associations of filaggrin gene loss-of-function variants and human papillomavirus-related cancer and pre-cancer in danish adults. PLoS One, 9: e99437.CrossRefGoogle Scholar
  32. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis- Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale S J, Compton JG, Di Giovanna JJ, Presland RB, Fleckman P, and McLean WH. 2006. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet, 38: 337–342.CrossRefPubMedGoogle Scholar
  33. Takada K. 2000. Epstein-barr virus and gastric carcinoma. Mol Pathol, 53: 255–261.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Thompson MP, Kurzrock R. 2004. Epstein-barr virus and cancer. Clin Cancer Res, 10: 803–821.CrossRefPubMedGoogle Scholar
  35. Venturutti L, Cordo Russo RI, Rivas MA, Mercogliano MF, Izzo F, Oakley RH, Pereyra MG, de Martino M, Proietti CJ, Yankilevich P, Roa JC, Guzmán P, Cortese E, Allemand DH, Huang TH, Charreau EH, Cidlowski JA, Schillaci R, Elizalde PV. 2016). MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene. doi: 10.1038/onc.2016.151.Google Scholar
  36. Wang J, Ying Y, Bo S, Li G, Yuan F. 2016. Differentially expressed microRNA-218 modulates the viability of renal cell carcinoma by regulating BCL9. Mol Med Rep, 14: 1829–1834.PubMedGoogle Scholar
  37. Wu J, Lei H, Zhang J, Chen X, Tang C, Wang W, Xu H, Xiao W, Gu W, Wu Y. 2016). Momordin Ic, a new natural SENP1 inhibitor, inhibits prostate cancer cell proliferation. Oncotarget. doi: 10.18632/oncotarget.10636.Google Scholar
  38. Wu MS, Shun CT, Wu CC, Hsu TY, Lin MT, Chang MC, Wang HP, and Lin JT. 2000. Epstein-barr virus-associated gastric carcinomas: Relation to h. Pylori infection and genetic alterations. Gastroenterology, 118: 1031–1038.PubMedGoogle Scholar
  39. Wu Y, Peng Y, Wu M, Zhang W, Zhang M, Xie R, Zhang P, Bai Y, Zhao J, Li A, Nan Q, Chen Y, Ren Y, Liu S, Wang J. 2016). Oncogene FOXK1 enhances invasion of colorectal carcinoma by inducing epithelial-mesenchymal transition. Oncotarget. doi: 10.18632/oncotarget.9457.Google Scholar
  40. Xie M, Sun M, Zhu YN, Xia R, Liu YW, Ding J, Ma HW, He XZ, Zhang ZH, Liu ZJ, Liu XH, De W. 2015. Long noncoding RNA HOXA-AS2 promotes gastric cancer proliferation by epigenetically silencing P21/PLK3/DDIT3 expression. Oncotarget, 6: 33587–33601.PubMedPubMedCentralGoogle Scholar
  41. Xu X, Xu L, Gao F, Wang J, Ye J, Zhou M, Zhu Y, Tao L. 2014. Identification of a novel gene fusion (BMX-ARHGAP) in gastric cardia adenocarcinoma. Diagn Pathol, 9: 218.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Zang WQ, Yang X, Wang T, Wang YY, Du YW, Chen XN, Li M, Zhao GQ. 2015. MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World J Gastroenterol, 21: 5867–5876.PubMedPubMedCentralGoogle Scholar
  43. Zhang W, Liu H, Liu Z, Zhu D, Amos CI, Fang S, Lee JE, Wei Q. 2015. Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma. Cancer Epidemiol Biomarkers Prev., 24: 1101–1110.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Zhang Y, Tian Y, Yu JJ, He J, Luo J, Zhang S, Tang CE, Tao YM. 2013. Overexpression of WDR62 is associated with centrosome amplification in human ovarian cancer. J Ovarian Res, 6: 55.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhao D, Liu S, Sun L, Zhao Z, Liu S, Kuang X, Shu J, Luo B. 2016. Glypican-4 gene polymorphism (rs1048369) and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma. Virus Res, 220: 52–56.CrossRefPubMedGoogle Scholar
  46. Zhao N, Yang K, Yang G, Chen D, Tang H, Zhao D, Zhao C. 2013. Aberrant expression of clock gene period1 and its correlations with the growth, proliferation and metastasis of buccal squamous cell carcinoma. 2013. PLoS One, 8: e55894.CrossRefGoogle Scholar
  47. Zheng L, Sun D, Fan W, Zhang Z, Li Q, Jiang T. 2015. Diagnostic value of SFRP1 as a favorable predictive and prognostic biomarker in patients with prostate cancer. PLoS One, 10: e0118276.Google Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Science+Business Media Singapore 2016

Authors and Affiliations

  • Xiaojing Kuang
    • 1
  • Lingling Sun
    • 2
  • Shuzhen Liu
    • 3
  • Zhenzhen Zhao
    • 1
  • Danrui Zhao
    • 1
  • Song Liu
    • 1
  • Bing Luo
    • 1
  1. 1.Department of Medical MicrobiologyQingdao University Medical CollegeQingdaoChina
  2. 2.Department of PathologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
  3. 3.Department of Blood TransfusionThe Affiliated Hospital of Qingdao UniversityQingdaoChina

Personalised recommendations