Tumor Biology

, Volume 36, Issue 4, pp 2551–2558 | Cite as

Significant association between upstream transcription factor 1 rs2516839 polymorphism and hepatocellular carcinoma risk: a case–control study

Research Article


Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high mortality rate. Upstream transcription factor 1 (USF1) is a ubiquitously expressed transcription factor that regulates the expression of genes involving in different biological processes, including cancer. The aim of this study is to examine the correlation between USF1 polymorphisms and HCC susceptibility. Ninety-four HCC patients and 100 healthy volunteers are recruited in our study. Tag single nucleotide polymorphisms (Tag-SNPs) were retrieved in the International HapMap Project Databases. Extraction of genomic DNAs was conducted with TaqMan Blood DNA kits. Genotyping of USF1 polymorphisms were carried out with TaqMan SNPs genotyping assay. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were calculated to evaluate the association between USF1 polymorphisms and HCC risk. All statistical analyses were performed with SPSS 20.0 software. Five tag-SNPs were identified to represent the genetic variants of USF1. Our results suggested that rs2516839 in the 5′UTR of USF1 was significantly associated with increased HCC risk (AA vs GG: OR = 3.15; 95 % CI 1.44–6.87; P = 0.003; GA + AA vs AA: OR = 1.85; 95 % CI 1.04–3.30; P = 0.034; AA vs GG + GA: OR = 2.96; 95 % CI 1.40–6.26; P = 0.004; A vs G: OR = 2.09; 9 % CI 1.35–3.23; P < 0.001). Although rs2073655 in the intron region of USF1 was also shown to be correlated with decreased HCC susceptibility in recessive model (TT vs CC + CT: OR = 0.40; 95 % CI 0.54–0.75; P = 0.004), this association was not conclusive. Our results indicated that the SNP of rs2516839 have close association with increased risk of HCC. Further studies may be needed to validate our results and gain insights into the pathological mechanism of USF1 gene in the HCC tumorigenesis.


USF1 Hepatocellular carcinoma Single nucleotide polymorphism Association 


Conflicts of interest



  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    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
  3. 3.
    El–Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.CrossRefPubMedGoogle Scholar
  6. 6.
    Santella RM, Wu HC. Environmental exposures and hepatocellular carcinoma. J Clin Transl Hepatol. 2013;1:138–43.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Dragani TA. Risk of HCC: genetic heterogeneity and complex genetics. J Hepatol. 2010;52:252–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Baron Y, Corre S, Mouchet N, Vaulont S, Prince S, Galibert M-D. USF1 is critical for maintaining genome integrity in response to UV-induced DNA photolesions. PLoS Genet. 2012;8:e1002470.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ikeda R, Nishizawa Y, Tajitsu Y, Minami K, Mataki H, Masuda S, et al. Regulation of major vault protein expression by upstream stimulating factor 1 in SW620 human colon cancer cells. Oncol Rep. 2014;31:197–201. doi: 10.3892/or.2013.2818.PubMedGoogle Scholar
  10. 10.
    Wu S, Mar-Heyming R, Dugum EZ, Kolaitis NA, Qi H, Pajukanta P, et al. Upstream transcription factor 1 influences plasma lipid and metabolic traits in mice. Hum Mol Genet. 2010;19:597–608. doi: 10.1093/hmg/ddp526.CrossRefPubMedGoogle Scholar
  11. 11.
    van Deursen D, Jansen H, Verhoeven AJ. Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2. Diabetologia. 2008;51:2078–87. doi: 10.1007/s00125-008-1125-6.CrossRefPubMedGoogle Scholar
  12. 12.
    Putt W, Palmen J, Nicaud V, Tregouet DA, Tahri-Daizadeh N, Flavell DM, et al. Variation in USF1 shows haplotype effects, gene:gene and gene:environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II. Hum Mol Genet. 2004;13:1587–97. doi: 10.1093/hmg/ddh168.CrossRefPubMedGoogle Scholar
  13. 13.
    Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet. 2004;36:371–6. doi: 10.1038/ng1320.CrossRefPubMedGoogle Scholar
  14. 14.
    Lee JC, Weissglas-Volkov D, Kyttala M, Sinsheimer JS, Jokiaho A, de Bruin TW, et al. USF1 contributes to high serum lipid levels in Dutch FCHL families and U.S. whites with coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;27:2222–7. doi: 10.1161/ATVBAHA.107.151530.CrossRefPubMedGoogle Scholar
  15. 15.
    Coon H, Xin Y, Hopkins PN, Cawthon RM, Hasstedt SJ, Hunt SC. Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides. Hum Genet. 2005;117:444–51. doi: 10.1007/s00439-005-1340-x.CrossRefPubMedGoogle Scholar
  16. 16.
    Holzapfel C, Baumert J, Grallert H, Müller A, Thorand B, Khuseyinova N, et al. Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002. Eur J Endocrinol. 2008;159:407–16.CrossRefPubMedGoogle Scholar
  17. 17.
    Laurila P-P, Naukkarinen J, Kristiansson K, Ripatti S, Kauttu T, Silander K, et al. Genetic association and interaction analysis of USF1 and APOA5 on lipid levels and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30:346–52.CrossRefPubMedGoogle Scholar
  18. 18.
    Kristiansson K, Ilveskoski E, Lehtimäki T, Peltonen L, Perola M, Karhunen PJ. Association analysis of allelic variants of USF1 in coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:983–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Naukkarinen J, Gentile M, Soro-Paavonen A, Saarela J, Koistinen HA, Pajukanta P, et al. USF1 and dyslipidemias: converging evidence for a functional intronic variant. Hum Mol Genet. 2005;14:2595–605.CrossRefPubMedGoogle Scholar
  20. 20.
    Corre S, Galibert MD. Upstream stimulating factors: highly versatile stress-responsive transcription factors. Pigment Cell Res. 2005;18:337–48. doi: 10.1111/j.1600-0749.2005.00262.x.CrossRefPubMedGoogle Scholar
  21. 21.
    Pezzolesi MG, Zbuk KM, Waite KA, Eng C. Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. Hum Mol Genet. 2007;16:1058–71. doi: 10.1093/hmg/ddm053.CrossRefPubMedGoogle Scholar
  22. 22.
    Bu Y, Gelman IH. v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex. J Biol Chem. 2007;282:26725–39. doi: 10.1074/jbc.M702885200.CrossRefPubMedGoogle Scholar
  23. 23.
    McMurray HR, McCance DJ. Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. J Virol. 2003;77:9852–61.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chang JT, Yang HT, Wang TC, Cheng AJ. Upstream stimulatory factor (USF) as a transcriptional suppressor of human telomerase reverse transcriptase (hTERT) in oral cancer cells. Mol Carcinog. 2005;44:183–92. doi: 10.1002/mc.20129.CrossRefPubMedGoogle Scholar
  25. 25.
    Jung HS, Kim KS, Chung YJ, Chung HK, Min YK, Lee MS, et al. USF inhibits cell proliferation through delay in G2/M phase in FRTL-5 cells. Endocr J. 2007;54:275–85.CrossRefPubMedGoogle Scholar
  26. 26.
    Luo X, Sawadogo M. Antiproliferative properties of the USF family of helix-loop-helix transcription factors. Proc Natl Acad Sci U S A. 1996;93:1308–13.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.CrossRefPubMedGoogle Scholar
  28. 28.
    Kwok P-Y. Single nucleotide polymorphisms. Totowa, NJ: Humana; 2003.Google Scholar
  29. 29.
    Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG. Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J. 1997;16:7091–104. doi: 10.1093/emboj/16.23.7091.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rada-Iglesias A, Ameur A, Kapranov P, Enroth S, Komorowski J, Gingeras TR, et al. Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders. Genome Res. 2008;18:380–92. doi: 10.1101/gr.6880908.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Shoulders CC, Naoumova RP. USF1 implicated in the aetiology of familial combined hyperlipidaemia and the metabolic syndrome. Trends Mol Med. 2004;10:362–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Singmann P, Baumert J, Herder C, Meisinger C, Holzapfel C, Klopp N, et al. Gene-gene interaction between APOA5 and USF1: two candidate genes for the metabolic syndrome. Obes Facts. 2009;2:235–42.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lee S-K, Kim H-J, Kim B-J, Jo Y-S, Park K-S, Baik H-W, et al. Body mass index is associated with USF1 haplotype in Korean premenopausal women. J Korean Med Sci. 2008;23:83–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Jaiswal AS, Narayan S. Upstream stimulating factor‐1 (USF1) and USF2 bind to and activate the promoter of the adenomatous polyposis coli (APC) tumor suppressor gene. J Cell Biochem. 2001;81:262–77.CrossRefPubMedGoogle Scholar
  35. 35.
    Davis PL, Miron A, Andersen LM, Iglehart JD, Marks JR. Isolation and initial characterization of the BRCA2 promoter. Oncogene. 1999;18:6000–12. doi: 10.1038/sj.onc.1202990.CrossRefPubMedGoogle Scholar
  36. 36.
    Luscher B, Larsson LG. The basic region/helix-loop-helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation. Oncogene. 1999;18:2955–66. doi: 10.1038/sj.onc.1202750.CrossRefPubMedGoogle Scholar
  37. 37.
    Reisman D, Rotter V. The helix-loop-helix containing transcription factor USF binds to and transactivates the promoter of the p53 tumor suppressor gene. Nucleic Acids Res. 1993;21:345–50.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Oncological SurgeryThe Second Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Department of Respiratory MedicineBethune International Peace HospitalShijiazhuangChina
  3. 3.Department of General SurgeryHandan HospitalHandanChina

Personalised recommendations