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.
Similar content being viewed by others
References
Bustin M (2001) Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci 26:152–153
Thomas J (2001) HMG1 and 2: architectural DNA-binding proteins. Biochem Soc Trans 29:395–401
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
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
Bianchi ME, Beltrame M, Paonessa G (1989) Specific recognition of cruciform DNA by nuclear protein HMG1. Science 243:1056–1059
Pil PM, Lippard SJ (1992) Specific binding of chromosomal protein HMG1 to DNA damaged by the anticancer drug cisplatin. Science 256:234–237
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
Agresti A, Bianchi ME (2003) HMGB proteins and gene expression. Curr Opin Genet Dev 13:170–178
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
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
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
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
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
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
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
Degryse B, de Virgilio M (2003) The nuclear protein HMGB1, a new kind of chemokine? FEBS Lett 553:11–17
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
Fages S, Nolo R, Huttunen HJ, Eskelinen E, Rauvala H (2000) Regulation of cell migration by amphoterin. J Cell Sci 113:611–620
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
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
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
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
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
Huttunen HJ, Rauvala H (2004) Amphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med 255:351–366
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-009-0305-0