Skip to main content
Log in

The expression of HMGB1 protein and its receptor RAGE in human malignant tumors

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein discovered to be released in the extracellular medium as a response to various stimuli and implicated in cancerogenesis. High HMGB1 levels are reported in a variety of tumor types, but there are few data relating HMGB1 to the histological grade or to a particular cell type and cellular localization. We studied the expression of HMGB1 protein in malignant human tumors of different differentiation level and in tumor metastasis. In all tumor tissues, the protein level is elevated. In moderately differentiated carcinomas, the localization of the protein is perinuclear, while in the low differentiated; there is a tendency for non-specific nuclear localization. HMGB1 protein and its receptor RAGE are identified as a ligand–receptor pair that plays an important role in regulating the invasiveness of tumor cells. RAGE is not produced in all of the tested tumor specimens. We found high level of expression in hepatocellular, colorectal, and breast cribriform carcinomas, but not in malignant testicular specimens. Probably, the RAGE synthesis is related to distinctive tumor types. In metastatic cells, RAGE exhibits higher level of expression losing its specific granular cytosolic pattern characteristic for the primary tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bustin M (2001) Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci 26:152–153

    Article  CAS  PubMed  Google Scholar 

  2. Thomas J (2001) HMG1 and 2: architectural DNA-binding proteins. Biochem Soc Trans 29:395–401

    Article  CAS  PubMed  Google Scholar 

  3. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195

    Article  CAS  PubMed  Google Scholar 

  4. Bianchi ME, Beltrame M (2000) Upwardly mobile proteins. Workshop: the role of HMG proteins in chromatin structure, gene expression and neoplasia. EMBO Rep 1:109–111

    Article  CAS  PubMed  Google Scholar 

  5. Bianchi ME, Beltrame M, Paonessa G (1989) Specific recognition of cruciform DNA by nuclear protein HMG1. Science 243:1056–1059

    Article  CAS  PubMed  Google Scholar 

  6. Pil PM, Lippard SJ (1992) Specific binding of chromosomal protein HMG1 to DNA damaged by the anticancer drug cisplatin. Science 256:234–237

    Article  CAS  PubMed  Google Scholar 

  7. Pasheva EA, Pashev IG, Favre A (1998) Preferential binding of high mobility group 1 protein to UV damaged DNA. J Biol Chem 273:24730–24736

    Article  CAS  PubMed  Google Scholar 

  8. Agresti A, Bianchi ME (2003) HMGB proteins and gene expression. Curr Opin Genet Dev 13:170–178

    Article  CAS  PubMed  Google Scholar 

  9. Zappavigna V, Falciola L, Helmer-Citterich M, Mavilio F, Bianchi ME (1996) HMG1 interacts with HOX proteins and enhances their DNA binding and transcriptional activation. EMBO J 15:4981–4991

    CAS  PubMed  Google Scholar 

  10. Jayaraman L, Moorthy NC, Murthy KG, Manley JL, Bustin M, Prives C (1998) High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev 12:462–472

    Article  CAS  PubMed  Google Scholar 

  11. Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, Edwards DP (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol Cell Biol 18:4471–4487

    CAS  PubMed  Google Scholar 

  12. Passalacqua M, Zicca A, Sparatore B, Patrone M, Melloni E, Pontremoli S (1997) Secretion and binding of HMG1 protein to the external surface of the membrane are required for murine erythroleukemia cell differentiation. FEBS Lett 400:275–279

    Article  CAS  PubMed  Google Scholar 

  13. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251

    Article  CAS  PubMed  Google Scholar 

  14. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360

    Article  CAS  PubMed  Google Scholar 

  15. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570

    Article  CAS  PubMed  Google Scholar 

  16. Degryse B, de Virgilio M (2003) The nuclear protein HMGB1, a new kind of chemokine? FEBS Lett 553:11–17

    Article  CAS  PubMed  Google Scholar 

  17. Degryse B, Bonaldi T, Scaffidi P, Müller S, Resnati M, Sanvito F, Arrigoni G, Bianchi ME (2001) The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 152:1197–1206

    Article  CAS  PubMed  Google Scholar 

  18. Fages S, Nolo R, Huttunen HJ, Eskelinen E, Rauvala H (2000) Regulation of cell migration by amphoterin. J Cell Sci 113:611–620

    CAS  PubMed  Google Scholar 

  19. Xiang Y, Wang D, Tanaka M, Suzuki M, Kiyokawa E, Igarashi H, Naito Y, Shen Q, Sugimura H (1997) Expression of high-mobility group-1 mRNA in human gastrointestinal adenocarcinoma and corresponding non-cancerous mucosa. Int J Cancer 74:1–6

    Article  CAS  PubMed  Google Scholar 

  20. Poser I, Golob M, Buettner R, Bossrehoff A (2003) Upregulation of HMG1 leads to melanoma inhibitory activity expression in malignant melanoma cells and contributes to their malignancy phenotype. Mol Cell Biol 23:2991–2998

    Article  CAS  PubMed  Google Scholar 

  21. Cabart P, Kalousek I, Jandova D, Hrkal Z (1995) Differential expression of nuclear HMG1, HMG2 proteins and H1(zero) histone in various blood cells. Cell Biochem Funct 13:125–133

    Article  CAS  PubMed  Google Scholar 

  22. Flohr A, Rogalla P, Meiboom M, Borrmann L, Krohn M, Thode-Halle B, Bullrdiek J (2001) Variation of HMGB1 expression in breast cancer. Anticancer Res 21:3881–3885

    CAS  PubMed  Google Scholar 

  23. Müller S, Ronfani L, Bianchi ME (2004) Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Int Med 255:332–343

    Article  Google Scholar 

  24. Huttunen HJ, Rauvala H (2004) Amphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med 255:351–366

    Article  CAS  PubMed  Google Scholar 

  25. Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, Ito R, Yokozaki H (2002) Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 196:163–170

    Article  CAS  PubMed  Google Scholar 

  26. Kuniyasu H, Chihara Y, Kondo H, Ohmori H, Ukai R (2003) Amphoterin induction in prostatic stromal cells by androgen deprivation is associated with metastatic prostate cancer. Oncol Rep 10:1863–1868

    CAS  PubMed  Google Scholar 

  27. Kuniyasu H, Chihara Y, Takahashi T (2003) Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep 10:445–448

    PubMed  Google Scholar 

  28. Kuniyasu H, Chihara Y, Kondo H (2003) Differential effects between amphoterin and advanced glycation end products on colon cancer cells. Int J Cancer 104:722–727

    Article  CAS  PubMed  Google Scholar 

  29. Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinami K, Kubota Y, Uemura H (2005) RAGE and its ligand amphoterin are over expressed and associated with prostate cancer development. Prostate 64:92–100

    Article  CAS  PubMed  Google Scholar 

  30. Elston C, Ellis IO (1998) Assessment of histological grade. In: Elston CW, Ellis IO (eds) The breast, vol 13. Churchill Livingstone, Edinburgh, pp 356–384

    Google Scholar 

  31. Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT (2007) Masquerader: high mobility group box-1 and cancer. Clin Cancer Res 13:2836–2848

    Article  CAS  PubMed  Google Scholar 

  32. Völp K, Brezniceanu ML, Bösser S, Brabletz T, Kirchner T, Göttel D, Joos S, Zörnig M (2006) Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas. Gut 55:234–242

    Article  PubMed  Google Scholar 

  33. Sasahira T, Akama Y, Fujii K, Kuniyasu H (2005) Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas. Virchows Arch 446:411–415

    Article  CAS  PubMed  Google Scholar 

  34. Balasubramani M, Day BW, Schoen RE, Getzenberg RH (2006) Altered expression and localization of creatine kinase B, heterogeneous nuclear ribonucleoprotein F, and high mobility group box 1 protein in the nuclear matrix associated with colon cancer. Cancer Res 66:763–769

    Article  CAS  PubMed  Google Scholar 

  35. Cheng C, Tsuneyama K, Kominami R, Shinohara H, Sakurai S, Yonekura H, Watanabe T, Takano Y, Yamamoto H, Yamamoto Y (2005) Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs. Mod Pathol 18:1385–1396

    Article  CAS  PubMed  Google Scholar 

  36. Bartling B, Hofmann HS, Weigle B, Silber RE, Simm A (2005) Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma. Carcinogenesis 26:293–301

    Article  CAS  PubMed  Google Scholar 

  37. Takada M, Hirata K, Ajiki T, Suzuki Y, Kuroda Y (2004) Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells. Hepatogastroenterology 51:928–930

    CAS  PubMed  Google Scholar 

  38. Riuzzi F, Sorci G, Donato R (2007) RAGE expression in rhabdomyosarcoma cells results in myogenic differentiation and reduced proliferation, migration, invasiveness, and tumor growth. Am J Pathol 171:947–961

    Article  CAS  PubMed  Google Scholar 

  39. Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-nB require he cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274:19919–19924

    Article  CAS  PubMed  Google Scholar 

  40. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3:955–1001

    Article  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gulubova and Dr. Vlaykova from the Medical Faculty, Tracian University, and Stara Zagora for the surgical specimens and fruitful advices. This study was supported by grant CRP/BUL 06-01 from International Centre for Genetic Engineering and Biotechnology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Evdokia Pasheva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kostova, N., Zlateva, S., Ugrinova, I. et al. The expression of HMGB1 protein and its receptor RAGE in human malignant tumors. Mol Cell Biochem 337, 251–258 (2010). https://doi.org/10.1007/s11010-009-0305-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-009-0305-0

Keywords

Navigation