High mobility group box 1 protein (HMGB1), a nuclear protein, can be translocated to the cytoplasm and secreted in colon cancer cells. However, the diagnostic significance of HMGB1 has not been evaluated in colorectal carcinomas. For this purpose, we have screened the expression and secretion of HMGB1 in 10 colon cancer cell lines and 1 control cell line and found that HMGB1 was detected in the culture medium. To evaluate the diagnostic value of HMGB1, we performed an enzyme-linked immunosorbent assay to measure HMGB1 levels and compared them to carcinoembryonic antigen (CEA) levels in the serum samples of 219 colorectal carcinoma patients and 75 healthy control subjects. We found that the serum HMGB1 level was increased by 1.5-fold in patients with colorectal carcinoma compared to those in healthy controls. When HMGB1 and CEA levels were compared, HMGB1 had similar efficacy as CEA regarding cancer detection (the sensitivity was 20.1% for HMGB1 vs. 25.6% for CEA, and the specificity was 96% for HMGB1 vs. 90.7% for CEA). Moreover, the diagnostic accuracy of HMGB1 for stage I cancer was significantly higher than that of CEA (sensitivity: 41.2% vs. 5.9%; specificity: 96% vs. 90.7). When we combined HMGB1 and CEA, the overall diagnostic sensitivity was higher than that of CEA alone (42% vs. 25.6%), and the diagnostic sensitivity for stage I was also elevated (47% vs. 5.9%). However, the prognosis of patients was not related with serum HMGB1 concentrations. Our findings indicate that serum HMGB1 levels are increased in a subset of colorectal carcinomas, suggesting their potential utility as a supportive diagnostic marker for colorectal carcinomas.
References
[1]
Goodwin GH, Sanders C, Johns EW (1973) A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 38: 14–19.
[2]
Bustin M (1999) Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol 19: 5237–5246.
[3]
Weir HM, Kraulis PJ, Hill CS, Raine AR, Laue ED, et al. (1993) Structure of the HMG box motif in the B-domain of HMG1. EMBO J 12: 1311–1319.
[4]
Youn JH, Shin JS (2006) Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol 177: 7889–7897.
[5]
Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, et al. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22: 5551–5560.
[6]
Thanos D, Maniatis T (1992) The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell 71: 777–789.
[7]
Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, et al. (2003) Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 23: 2225–2238.
[8]
Fashena SJ, Reeves R, Ruddle NH (1992) A poly(dA-dT) upstream activating sequence binds high-mobility group I protein and contributes to lymphotoxin (tumor necrosis factor-beta) gene regulation. Mol Cell Biol 12: 894–903.
[9]
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.
[10]
Tarbe N, Evtimova V, Burtscher H, Jarsch M, Alves F, et al. (2001) Transcriptional profiling of cell lines derived from an orthotopic pancreatic tumor model reveals metastasis-associated genes. Anticancer Res 21: 3221–3228.
[11]
Maeda S, Hikiba Y, Shibata W, Ohmae T, Yanai A, et al. (2007) Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer. Biochem Biophys Res Commun 360: 394–400.
[12]
Leman ES, Madigan MC, Brunagel G, Takaha N, Coffey DS, et al. (2003) Nuclear matrix localization of high mobility group protein I(Y) in a transgenic mouse model for prostate cancer. J Cell Biochem 88: 599–608.
[13]
Dolde CE, Mukherjee M, Cho C, Resar LM (2002) HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat 71: 181–191.
[14]
Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, et al. (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405: 354–360.
[15]
Candolfi M, Yagiz K, Foulad D, Alzadeh GE, Tesarfreund M, et al. (2009) Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res 15: 4401–4414.
[16]
Ito N, DeMarco RA, Mailliard RB, Han J, Rabinowich H, et al. (2007) Cytolytic cells induce HMGB1 release from melanoma cell lines. J Leukoc Biol 81: 75–83.
[17]
Kang HJ, Lee H, Choi HJ, Youn JH, Shin JS, et al. (2009) Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers. Lab Invest 89: 948–959.
[18]
Lim SC, Choi JE, Kim CH, Duong HQ, Jeong GA, et al. (2007) Ethyl pyruvate induces necrosis-to-apoptosis switch and inhibits high mobility group box protein 1 release in A549 lung adenocarcinoma cells. Int J Mol Med 20: 187–192.
[19]
Cheng BQ, Jia CQ, Liu CT, Lu XF, Zhong N, et al. (2008) Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis 40: 446–452.
[20]
Chung HW, Lee SG, Kim H, Hong DJ, Chung JB, et al. (2009) Serum high mobility group box-1 (HMGB1) is closely associated with the clinical and pathologic features of gastric cancer. J Transl Med 7: 38.
[21]
Naumnik W, Nilklinska W, Ossolinska M, Chyczewska E (2009) Serum levels of HMGB1, survivin, and VEGF in patients with advanced non-small cell lung cancer during chemotherapy. Folia Histochem Cytobiol 47: 703–709.
[22]
Shang GH, Jia CQ, Tian H, Xiao W, Li Y, et al. (2009) Serum high mobility group box protein 1 as a clinical marker for non-small cell lung cancer. Respir Med 103: 1949–1953.
[23]
Sheng X, Du X, Zhang X, Li D, Lu C, et al. (2009) Clinical value of serum HMGB1 levels in early detection of recurrent squamous cell carcinoma of uterine cervix: comparison with serum SCCA, CYFRA21-1, and CEA levels. Croat Med J 50: 455–464.
[24]
Volp K, Brezniceanu ML, Bosser S, Brabletz T, Kirchner T, et al. (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.
[25]
Dudek AZ, Mahaseth H (2005) Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Cancer Invest 23: 193–200.
[26]
Leconte A, Garambois V, Ychou M, Robert B, Pourquier D, et al. (1999) Involvement of circulating CEA in liver metastases from colorectal cancers re-examined in a new experimental model. Br J Cancer 80: 1373–1379.
[27]
Fakih MG, Padmanabhan A (2006) CEA monitoring in colorectal cancer. What you should know. Oncology (Williston Park) 20: 579–587; discussion 588, 594, 596 passim.
[28]
Sung JJ, Lau JY, Goh KL, Leung WK (2005) Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 6: 871–876.
[29]
Kim HJ, Yu MH, Kim H, Byun J, Lee C (2008) Noninvasive molecular biomarkers for the detection of colorectal cancer. BMB Rep 41: 685–692.
[30]
Bast RC Jr, Ravdin P, Hayes DF, Bates S, Fritsche H Jr, et al. (2001) 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19: 1865–1878.
[31]
Tang D, Kang R, Zeh HJ 3rd, Lotze MT (2010) High-mobility group box 1 and cancer. Biochim Biophys Acta 1799: 131–140.
[32]
Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220: 35–46.
[33]
Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5: 331–342.
[34]
Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, et al. (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5: 825–830.
[35]
Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106: 609–616.
[36]
Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, et al. (2007) Masquerader: high mobility group box-1 and cancer. Clin Cancer Res 13: 2836–2848.
[37]
Evans A, Lennard TW, Davies BR (2004) High-mobility group protein 1(Y): metastasis-associated or metastasis-inducing? J Surg Oncol 88: 86–99.
[38]
Poser I, Golob M, Buettner R, Bosserhoff AK (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.
[39]
Wanebo HJ, Rao B, Pinsky CM, Hoffman RG, Stearns M, et al. (1978) Preoperative carcinoembryonic antigen level as a prognostic indicator in colorectal cancer. N Engl J Med 299: 448–451.
[40]
Holten-Andersen MN, Christensen IJ, Nielsen HJ, Stephens RW, Jensen V, et al. (2002) Total levels of tissue inhibitor of metalloproteinases 1 in plasma yield high diagnostic sensitivity and specificity in patients with colon cancer. Clin Cancer Res 8: 156–164.
[41]
Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, et al. (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13: 1050–1059.
[42]
Lee H, Shin N, Song M, Kang UB, Yeom J, et al. (2010) Analysis of nuclear high mobility group box 1 (HMGB1)-binding proteins in colon cancer cells: clustering with proteins involved in secretion and extranuclear function. J Proteome Res 9: 4661–4670.
[43]
Yao X, Zhao G, Yang H, Hong X, Bie L, et al. (2010) Overexpression of high-mobility group box 1 correlates with tumor progression and poor prognosis in human colorectal carcinoma. J Cancer Res Clin Oncol 136: 677–684.
[44]
DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44: 837–845.
[45]
Chen YD, Zheng S, Yu JK, Hu X (2004) Artificial neural networks analysis of surface-enhanced laser desorption/ionization mass spectra of serum protein pattern distinguishes colorectal cancer from healthy population. Clin Cancer Res 10: 8380–8385.
[46]
Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, et al. (1993) An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270: 943–947.
