Tumor Biology

, Volume 36, Issue 2, pp 675–683 | Cite as

Lactotransferrin could be a novel independent molecular prognosticator of nasopharyngeal carcinoma

  • Wenling Zhang
  • Songqing Fan
  • Guoying Zou
  • Lei Shi
  • Zhaoyang Zeng
  • Jian Ma
  • Yanhong Zhou
  • Xiayu Li
  • Xinlin Zhang
  • Xiaoling Li
  • Ming Tan
  • Wei Xiong
  • Guiyuan Li
Research Article

Abstract

Lactotransferrin (LTF), also known as lactoferrin, is a key component of innate immune defense. We previously reported that LTF was downregulated in nasopharyngeal carcinoma (NPC) and could suppress NPC cell proliferation. However, the relevance of the relationship between LTF expression and NPC clinical outcome has not been reported. This study aims to assess the possible correlations between LTF expression and clinical parameters and its potential prognostic predictive ability in the outcomes of patients with NPC. Complementary DNA (cDNA) microarray, quantitative real-time PCR (qRT-PCR), and immunohistochemistry (IHC) results suggested that LTF expression was significantly downregulated in NPC tissues compared to non-NPC tissues. LTF was negatively correlated with lymph node metastasis (P = 0.042), T stage (P < 0.001), clinical tumor-node-metastasis (TNM) stage (P = 0.022), and EBV-encoded RNA 1 (EBER-1) expression (r = −.167, P = 0.016). A survival analysis of 108 patients with NPC revealed that positive expression of LTF could predict a good prognosis [disease-free survival (DFS): P = 0.043, overall survival (OS): P = 0.040]. Multivariable analysis revealed that LTF could independently predict prognosis (DFS: HR = 0.414, P = 0.003; OS: HR = 0.309, P = 0.005). These observations indicated that LTF is a potential prognostic factor of NPC.

Keywords

Nasopharyngeal carcinoma (NPC) LTF Prognosis 

Abbreviations

NPC

Nasopharyngeal carcinoma

IHC

Immunohistochemistry

LTF

Lactotransferrin

Notes

Conflicts of interest

None

Funding sources

This work was supported by the China Scholarship Council (CSC) and National Natural Science Foundation of China (Grant Nos. 30871282, 81071644, 81172189, 81272298, 81372907, 81472531, and 91229122), the Hunan Province Natural Science Foundation of China (Grant Nos. 14JJ1010 and 12JJ2044), and the Hunan Province Science and the Technology Foundation of China (Grant No. 2012FJ6073).

Supplementary material

13277_2014_2650_MOESM1_ESM.doc (1.1 mb)
Supplemental Table 1 (DOC 1174 kb)

References

  1. 1.
    Alexander DB, Iigo M, Yamauchi K, Suzui M, Tsuda H. Lactoferrin: an alternative view of its role in human biological fluids. Biochem Cell Biol. 2012;90:279–306.CrossRefPubMedGoogle Scholar
  2. 2.
    Gonzalez-Chavez SA, Arevalo-Gallegos S, Rascon-Cruz Q. Lactoferrin: structure, function and applications. Int J Antimicrob Agents. 2009;33:301.CrossRefPubMedGoogle Scholar
  3. 3.
    Legrand D, Mazurier J. A critical review of the roles of host lactoferrin in immunity. Biometals. 2010;23:365–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Rodrigues L, Teixeira J, Schmitt F, Paulsson M, Mansson HL. Lactoferrin and cancer disease prevention. Crit Rev Food Sci Nutr. 2009;49:203–17.CrossRefPubMedGoogle Scholar
  5. 5.
    Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin. A critical overview. Cell Mol Life Sci. 2005;62:2540–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Huang HB, Deng M, Zheng Y, Ma J, Zhang WL, Zhou YH, et al. Innate immune protein lactotransferrin prevents initiation and arrests progression of nasopharyngeal carcinoma. Prog Biochem Biophys. 2013;40:319–24.Google Scholar
  7. 7.
    Li WY, Li QW, Han ZS, Jiang ZL, Yang H, Li J, et al. Growth suppression effects of recombinant adenovirus expressing human lactoferrin on cervical cancer in vitro and in vivo. Cancer Biother Radiopharm. 2011;26:477–83.CrossRefPubMedGoogle Scholar
  8. 8.
    Yi HM, Li H, Peng D, Zhang HJ, Wang L, Zhao M, et al. Genetic and epigenetic alterations of LTF at 3p21.3 in nasopharyngeal carcinoma. Oncol Res. 2006;16:261–72.PubMedGoogle Scholar
  9. 9.
    Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S. Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer. 2006;119:99–107.CrossRefPubMedGoogle Scholar
  10. 10.
    Yang Y, Li J, Szeles A, Imreh MP, Kost-Alimova M, Kiss H, et al. Consistent downregulation of human lactoferrin gene, in the common eliminated region 1 on 3p21.3, following tumor growth in severe combined immunodeficient (SCID) mice. Cancer Lett. 2003;191:155–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Xiao Y, Monitto CL, Minhas KM, Sidransky D. Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells. Clin Cancer Res. 2004;10:8683–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou Y, Zeng Z, Zhang W, Xiong W, Wu M, Tan Y, et al. Lactotransferrin: a candidate tumor suppressor-deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway. Int J Cancer. 2008;123:2065–72.CrossRefPubMedGoogle Scholar
  13. 13.
    Deng M, Zhang W, Tang H, Ye Q, Liao Q, Zhou Y, et al. Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms. Oncogene. 2013;32:4273–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Zeng Z, Zhou Y, Xiong W, Luo X, Zhang W, Li X, et al. Analysis of gene expression identifies candidate molecular markers in nasopharyngeal carcinoma using microdissection and cDNA microarray. J Cancer Res Clin Oncol. 2007;133:71–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Zeng ZY, Zhou YH, Zhang WL, Xiong W, Fan SQ, Li XL, et al. Gene expression profiling of nasopharyngeal carcinoma reveals the abnormally regulated Wnt signaling pathway. Hum Pathol. 2007;38:120–33.CrossRefPubMedGoogle Scholar
  16. 16.
    Russo G, Zegar C, Giordano A. Advantages and limitations of microarray technology in human cancer. Oncogene. 2003;22:6497–507.CrossRefPubMedGoogle Scholar
  17. 17.
    Hoheisel JD. Microarray technology: beyond transcript profiling and genotype analysis. Nat Rev Genet. 2006;7:200–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Zeng Z, Huang H, Zhang W, Xiang B, Zhou M, Zhou Y, et al. Nasopharyngeal carcinoma: advances in genomics and molecular genetics. Sci China Life Sci. 2011;54:966–75.CrossRefPubMedGoogle Scholar
  19. 19.
    Liao Q, Zeng Z, Guo X, Li X, Wei F, Zhang W, et al. LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation. Oncogene. 2014;33:2098–109.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang Y, Liao Q, Wei F, Li X, Zhang W, Fan S, et al. LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways. PLoS One. 2013;8:e62869.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang W, Zeng Z, Wei F, Chen P, Schmitt DC, Fan S, et al. SPLUNC1 is associated with nasopharyngeal carcinoma prognosis and plays an important role in ATRA-induced growth inhibition and differentiation in nasopharyngeal cancer cells. FEBS J. 2014. doi: 10.1111/febs.13020.Google Scholar
  22. 22.
    Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5:845–56.CrossRefPubMedGoogle Scholar
  24. 24.
    Sriuranpong V, Mutirangura A, Gillespie JW, Patel V, Amornphimoltham P, Molinolo AA, et al. Global gene expression profile of nasopharyngeal carcinoma by laser capture microdissection and complementary DNA microarrays. Clin Cancer Res. 2004;10:4944–58.CrossRefPubMedGoogle Scholar
  25. 25.
    Sengupta S, den Boon JA, Chen IH, Newton MA, Dahl DB, Chen M, et al. Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma. Cancer Res. 2006;66:7999–8006.CrossRefPubMedGoogle Scholar
  26. 26.
    Tang K, Wei F, Bo H, Huang HB, Zhang WL, Gong ZJ, et al. Cloning and functional characterization of a novel long non-coding RNA gene associated with hepatocellular carcinoma. Prog Biochem Biophys. 2014;41:153–62.Google Scholar
  27. 27.
    Jacquemier J, Ginestier C, Rougemont J, Bardou VJ, Charafe-Jauffret E, Geneix J, et al. Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res. 2005;65:767–79.PubMedGoogle Scholar
  28. 28.
    Xiong W, Wu X, Starnes S, Johnson SK, Haessler J, Wang S, et al. An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood. 2008;112:4235–46.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fan SQ, Ma J, Zhou J, Xiong W, Xiao BY, Zhang WL, et al. Differential expression of Epstein-Barr virus-encoded RNA and several tumor-related genes in various types of nasopharyngeal epithelial lesions and nasopharyngeal carcinoma using tissue microarray analysis. Hum Pathol. 2006;37:593–605.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang W, Zeng Z, Fan S, Wang J, Yang J, Zhou Y, et al. Evaluation of the prognostic value of TGF-beta superfamily type I receptor and TGF-beta type II receptor expression in nasopharyngeal carcinoma using high-throughput tissue microarrays. J Mol Histol. 2012;43:297–306.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang W, Huang C, Gong Z, Zhao Y, Tang K, Li X, et al. Expression of LINC00312, a long intergenic non-coding RNA, is negatively correlated with tumor size but positively correlated with lymph node metastasis in nasopharyngeal carcinoma. J Mol Histol. 2013;44:545–54.CrossRefPubMedGoogle Scholar
  32. 32.
    Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Kochli OR, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001;159:2249–56.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Res. 2001;52:225–39.CrossRefPubMedGoogle Scholar
  34. 34.
    Xiong W, Zeng ZY, Xia JH, Xia K, Shen SR, Li XL, et al. A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma. Cancer Res. 2004;64:1972–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Zeng Z, Zhou Y, Zhang W, Li X, Xiong W, Liu H, et al. Family-based association analysis validates chromosome 3p21 as a putative nasopharyngeal carcinoma susceptibility locus. Genet Med. 2006;8:156–60.CrossRefPubMedGoogle Scholar
  36. 36.
    Ghosh S, Ghosh A, Maiti GP, Alam N, Roy A, Roy B, et al. Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: correlation with progression and prognosis. Int J Cancer. 2008;123:2594–604.CrossRefPubMedGoogle Scholar
  37. 37.
    Gong ZJ, Huang HB, Xu K, Liang F, Li XL, Zeng ZY, et al. Advances in microRNAs and TP53 gene regulatory network. Prog Biochem Biophys. 2012;39:1133–44.CrossRefGoogle Scholar
  38. 38.
    Deng M, Ye Q, Qin Z, Zheng Y, He W, Tang H, et al. MiR-214 promotes tumorigenesis by targeting lactotransferrin in nasopharyngeal carcinoma. Tumour Biol. 2013;34:1793–800.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen P, Guo X, Zhou H, Zhang W, Zeng Z, Liao Q, et al. SPLUNC1 regulates cell progression and apoptosis through the miR-141-PTEN/p27 pathway, but is hindered by LMP1. PLoS One. 2013;8:e56929.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zhang W, Zeng Z, Zhou Y, Xiong W, Fan S, Xiao L, et al. Identification of aberrant cell cycle regulation in Epstein-Barr virus-associated nasopharyngeal carcinoma by cDNA microarray and gene set enrichment analysis. Acta Biochim Biophys Sin (Shanghai). 2009;41:414–28.CrossRefGoogle Scholar
  41. 41.
    Zeng Z, Huang H, Huang L, Sun M, Yan Q, Song Y, et al. Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas. Sci China Life Sci. 2014;57:315–26.CrossRefPubMedGoogle Scholar
  42. 42.
    Gong Z, Zhang S, Zhang W, Huang H, Li Q, Deng H, et al. Long non-coding RNAs in cancer. Sci China Life Sci. 2012;55:1120–4.CrossRefPubMedGoogle Scholar
  43. 43.
    Weiss LM, Chen YY. EBER in situ hybridization for Epstein-Barr virus. Methods Mol Biol. 2013;999:223–30.CrossRefPubMedGoogle Scholar
  44. 44.
    Wei F, Li XY, Li XL, Zhang WL, Liao QJ, Zeng Y, et al. The effect and mechanism of PLUNC protein family against inflammation and carcinogenesis of nasopharyngeal carcinoma. Prog Biochem Biophys. 2014;41:24–31.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Wenling Zhang
    • 1
    • 2
    • 3
  • Songqing Fan
    • 4
  • Guoying Zou
    • 2
  • Lei Shi
    • 4
  • Zhaoyang Zeng
    • 1
    • 3
    • 5
  • Jian Ma
    • 1
    • 3
    • 5
  • Yanhong Zhou
    • 1
    • 3
    • 5
  • Xiayu Li
    • 5
  • Xinlin Zhang
    • 2
  • Xiaoling Li
    • 1
    • 3
    • 5
  • Ming Tan
    • 6
  • Wei Xiong
    • 1
  • Guiyuan Li
    • 1
  1. 1.Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
  2. 2.Department of Medical Laboratory Science, Xiangya School of MedicineCentral South UniversityChangshaChina
  3. 3.Key Laboratory of Carcinogenesis of Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research InstituteCentral South UniversityChangshaChina
  4. 4.Department of Pathology, Second Xiangya HospitalCentral South UniversityChangshaChina
  5. 5.Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya HospitalCentral South UniversityChangshaChina
  6. 6.Mitchell Cancer InstituteUniversity of South AlabamaMobileUSA

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