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Medical Oncology

, 31:53 | Cite as

Decreased ITIH5 expression is associated with poor prognosis in primary gastric cancer

  • Cong Mai
  • Jing-jing Zhao
  • Xiao-feng Tang
  • Wei Wang
  • Ke Pan
  • Qiu-zhong Pan
  • Xiao-fei Zhang
  • Shan-shan Jiang
  • Bai-wei Zhao
  • Yuan-fang Li
  • Jian-chuan XiaEmail author
  • Zhi-wei ZhouEmail author
Original Paper

Abstract

Inter-α-trypsin inhibitors (ITIs) are a family of serine protease inhibitors that comprise one light chain and a variable set of heavy chains (ITI heavy chains, ITIHs). ITIH5 is a new member of the ITIH family that contains two domains conserved in all known ITIHs: vault protein IT and von Willebrand type A. Recent studies suggest that ITIH5 expression may be altered in certain types of cancer. This study aimed to investigate ITIH5 expression in clinical tumor specimens from gastric cancer patients and its prognostic value for gastric cancer. ITIH5 expression was detected in fresh gastric cancer tissues (T) and the matched adjacent non-tumor tissues (ANT) using real-time quantitative reverse transcription-PCR and Western blotting. ITIH5 expression was retrospectively detected in 331 paraffin-embedded, banked samples using immunohistochemical staining. ITIH5 mRNA and protein expression was significantly downregulated in gastric cancer tissues compared to the ANT. There was a significant association between ITIH5 expression and histological grade (P = 0.020), N classification (P = 0.047), and clinical stage (P = 0.011). Patients with low ITIH5 expression had shorter survival compared to those with high ITIH5 expression. Multivariate analysis showed that ITIH5 expression was an independent prognostic factor for overall survival of gastric cancer patients (P = 0.034). Our data suggest that ITIH5 could play an important role in gastric cancer and may serve as a valuable prognostic biomarker and potential molecular therapy target for gastric cancer.

Keywords

Inter-α-trypsin inhibitor heavy chain-5 (ITIH5) Gastric cancer Prognostic marker Survival 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China Grant 30973398.

Conflict of interest

None.

References

  1. 1.
    Jinawath N, Furukawa Y, Hasegawa S, et al. Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genome-wide cDNA microarray. Oncogene. 2004;23(40):6830–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Li YF, Wang DD, Zhao BW, et al. Poor prognosis of gastric adenocarcinoma with decreased expression of AHRR. PLoS ONE. 2012;7(8):e43555.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Tay ST, Leong SH, Yu K, et al. A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes. Cancer Res. 2003;63(12):3309–16.PubMedGoogle Scholar
  4. 4.
    Yang XB, Zhao JJ, Huang CY, et al. Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients. PLoS ONE. 2013;8(10):e78158.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Wang P, Mai C, Wei YL, et al. Decreased expression of the mitochondrial metabolic enzyme aconitase (ACO2) is associated with poor prognosis in gastric cancer. Med Oncol. 2013;30(2):552.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen Y, Pan K, Li S, et al. Decreased expression of V-set and immunoglobulin domain containing 1 (VSIG1) is associated with poor prognosis in primary gastric cancer. J Surg Oncol. 2012;106(3):286–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Miao R, Guo X, Zhi Q, et al. VEZT, a novel putative tumor suppressor, suppresses the growth and tumorigenicity of gastric cancer. PLoS ONE. 2013;8(9):e74409.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Kim K, Chun KH, Suh PG, Kim IH. Alterations in cell proliferation related gene expressions in gastric cancer. Crit Rev Eukaryot Gene Expr. 2011;21(3):237–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Saeki N, Ono H, Sakamoto H, Yoshida T. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci. 2013;104(1):1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Veeck J, Chorovicer M, Naami A, et al. The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. Oncogene. 2008;27(6):865–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Wei B, Song Y, Zhang Y, Hu M. microRNA-449a functions as a tumor-suppressor in gastric adenocarcinoma by targeting Bcl-2. Oncol Lett. 2013;6(6):1713–8.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Himmelfarb M, Klopocki E, Grube S, et al. ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer. Cancer Lett. 2004;204(1):69–77.PubMedCrossRefGoogle Scholar
  13. 13.
    Oing C, Jost E, Dahl E, Wilop S, Brummendorf TH, Galm O. Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia. Clin Epigenetics. 2011;2(2):419–23.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Diarra-Mehrpour M, Bourguignon J, Sesboue R, et al. Human plasma inter-alpha-trypsin inhibitor is encoded by four genes on three chromosomes. Eur J Biochem. 1989;179(1):147–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Diarra-Mehrpour M, Sarafan N, Bourguignon J, Bonnet F, Bost F, Martin JP. Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic organization, promoter analysis, and gene linkage. J Biol Chem. 1998;273(41):26809–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Hamm A, Veeck J, Bektas N, et al. Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: a systematic expression analysis. BMC Cancer. 2008;8:25.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Lu Y, Liu P, Wen W, et al. Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models. Am J Transl Res. 2010;3(1):8–27.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Pita JM, Banito A, Cavaco BM, Leite V. Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas. Br J Cancer. 2009;101(10):1782–91.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Huang L, Yoneda M, Kimata K. A serum-derived hyaluronan-associated protein (SHAP) is the heavy chain of the inter alpha-trypsin inhibitor. J Biol Chem. 1993;268(35):26725–30.PubMedGoogle Scholar
  20. 20.
    Kobayashi H, Gotoh J, Hirashima Y, Fujie M, Sugino D, Terao T. Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem. 1995;270(14):8361–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhao M, Yoneda M, Ohashi Y, et al. Evidence for the covalent binding of SHAP, heavy chains of inter-alpha-trypsin inhibitor, to hyaluronan. J Biol Chem. 1995;270(44):26657–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Paris S, Sesboue R, Delpech B, et al. Inhibition of tumor growth and metastatic spreading by overexpression of inter-alpha-trypsin inhibitor family chains. Int J Cancer. 2002;97(5):615–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Nagini S. Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 2012;4(7):156–69.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Zouridis H, Deng N, Ivanova T, et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med. 2012;4(156):156ra140.PubMedCrossRefGoogle Scholar
  25. 25.
    Miotto E, Sabbioni S, Veronese A, et al. Frequent aberrant methylation of the CDH4 gene promoter in human colorectal and gastric cancer. Cancer Res. 2004;64(22):8156–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Graff JR, Herman JG, Lapidus RG, et al. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 1995;55(22):5195–9.PubMedGoogle Scholar
  27. 27.
    Bachman KE, Herman JG, Corn PG, et al. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res. 1999;59(4):798–802.PubMedGoogle Scholar
  28. 28.
    Shao G, Berenguer J, Borczuk AC, Powell CA, Hei TK, Zhao Y. Epigenetic inactivation of Betaig-h3 gene in human cancer cells. Cancer Res. 2006;66(9):4566–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Cong Mai
    • 1
    • 2
  • Jing-jing Zhao
    • 1
    • 3
  • Xiao-feng Tang
    • 4
  • Wei Wang
    • 1
    • 2
  • Ke Pan
    • 1
  • Qiu-zhong Pan
    • 1
  • Xiao-fei Zhang
    • 1
  • Shan-shan Jiang
    • 1
  • Bai-wei Zhao
    • 1
    • 2
  • Yuan-fang Li
    • 1
    • 2
  • Jian-chuan Xia
    • 1
    • 3
    Email author
  • Zhi-wei Zhou
    • 1
    • 2
    Email author
  1. 1.State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  2. 2.Department of Gastric and Pancreatic SurgerySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  3. 3.Department of BiotherapySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  4. 4.Department of Ultrasound, Huangpu Clinical Medical CenterThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China

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