High expression of high mobility group box 1 (hmgb1) predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy

Journal of Translational Medicine

Minshan Chen¹  Li Xu¹  Hengjun Gao¹  Zhenwei Peng¹  Yaojun Zhang¹  Furong Liu¹ 

[1] State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China

关键词: Prognostic factor;    Prognosis;    Hepatectomy;    Hepatocellular carcinoma;    High mobility group box 1;   

Others  :  1205946
DOI  :  10.1186/1479-5876-10-135

 received in 2012-01-21, accepted in 2012-06-15,  发布年份 2012

【 摘 要 】

Background

High mobility group box 1(HMGB1) overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in hepatocellular carcinoma (HCC) remains unclear. The aim of present study was to analyze HMGB1 protein expression in tumor, para-tumor and normal tissue and to assess its prognostic significance for HCC after curative hepatectomy.

Methods

The levels of HMGB1 mRNA and protein in tumor, para-tumor and normal tissue were evaluated in 11 HCC cases by Reverse Transcription-polymerase chain reaction (RT-PCR) and Western blot. Additionally, HMGB1 protein expression in 161 HCC was analyzed by immunohistochemistry and correlated with clinicopathological characteristics and survivals. Student’s t-test, spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.

Results

By RT-PCR and Western blot, the levels of HMGB1 mRNA and protein were significantly higher in HCC, compared to that in para-tumor (p < 0.001) and normal tissue (p < 0.001). Immunohistochemical staining revealed that high expression of HMGB1 was detected in 42.9% (69/161) HCC cases. High expression of HMGB1 was significantly associated with incomplete encapsulation (p = 0.035) and advanced TNM stage (p = 0.036). Multivariate analysis showed that high expression of HMGB1 was an independent prognostic factor for both overall (p = 0.009, HR = 1.834, 95%CI: 1.167-2.881) and disease-free survival (p = 0.018, HR = 1.622, 95%CI: 1.088-2.419), along with tumor size. Subgroup analysis revealed that high expression of HMGB1 predicted poorer overall survival only for tumor >5 cm (p = 0.031), but not for tumor ≤5 cm (p = 0.101).

Conclusions

HMGB1 protein might contribute to the malignant progression of HCC, high expression of HMGB1 predicts poor prognosis for patients with HCC after curative hepatectomy, especially for patients with tumor >5 cm.

【 授权许可】

   
2012 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005, 42:1208-1236.
• [3]Llovet JM: Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 2005, 40:225-235.
• [4]Bruix J, Boix L, Sala M, Llovet JM: Focus on hepatocellular carcinoma. Cancer Cell 2004, 5:215-219.
• [5]Bustin M, Hopkins RB, Isenberg I: Immunological relatedness of high mobility group chromosomal proteins from calf thymus. J Biol Chem 1978, 253:1694-1699.
• [6]Luan ZG, Zhang H, Yang PT, Ma XC, Zhang C, Guo RX: HMGB1 activates nuclear factor-κB signaling by RAGE and increases the production of TNF-α in human umbilical vein endothelial cells. Immunobiology 2010, 215:956-962.
• [7]Stros M, Ozaki T, Bacikova A, Kageyama H, Nakagawara A: HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequencespecific transactivation from the human Bax gene promoter. J Biol Chem 2002, 277:7157-7164.
• [8]Zayed H, Izsvák Z, Khare D, Heinemann U, Ivics Z: The DNA-bending protein HMGB1 is a cellular cofactor of Sleeping Beauty transposition. Nucleic Acids Res 2003, 31:2313-2322.
• [9]Naghavi MH, Nowak P, Andersson J, Sönnerborg A, Yang H, Tracey KJ, Vahlne A: Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner. Virology 2003, 314:179-189.
• [10]Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002, 418:191-195.
• [11]Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G, Zitvogel L: Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res 2008, 68:4026-4030.
• [12]Semino C, Angelini G, Poggi A, Rubartelli A: 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 2005, 106:609-616.
• [13]Penzo M, Molteni R, Suda T, Samaniego S, Raucci A, Habiel DM, Miller F, Jiang HP, Li J, Pardi R, Palumbo R, Olivotto E, Kew RR, Bianchi ME, Marcu KB: Inhibitor of NF-kappa B kinases alpha and beta are both essential for high mobility group box 1-mediated chemotaxis. J Immunol 2010, 184:4497-4509.
• [14]Tafani M, Schito L, Pellegrini L, Villanova L, Marfe G, Anwar T, Rosa R, Indelicato M, Fini M, Pucci B, Russo MA: Hypoxia-increased RAGE and P2X7R expression regulates tumor cell invasion through phosphorylation of Erk1/2 and Akt and nuclear translocation of NF-{kappa}B. Carcinogenesis 2011, 32:1167-1175.
• [15]Yang J, Chen L, Yang J, Ding J, Rong H, Dong W, Li X: High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation. Mol Biol Rep 2011,  : . in press
• [16]Qin YH, Dai SM, Tang GS, Zhang J, Ren D, Wang ZW, Shen Q: HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. J Immunol 2009, 183:6244-6250.
• [17]Tang D, Kang R, Zeh HJ, Lotze MT: High-mobility group box 1 and cancer. Biochim Biophys Acta 2010, 1799:131-140.
• [18]Yao X, Zhao G, Yang H, Hong X, Bie L, Liu G: Overexpression of high-mobility group box 1 correlates with tumor progression and poor prognosis in human colorectal carcinoma. J Cancer Res Clin Oncol 2010, 136:677-684.
• [19]Bao G, Qiao Q, Zhao H, He X: Prognostic value of HMGB1 overexpression in resectable gastric adenocarcinomas. World J Surg Oncol 2010, 8:52. BioMed Central Full Text
• [20]Wu D, Ding Y, Wang S, Zhang Q, Liu L: Increased expression of high mobility group box 1 (HMGB1) is associated with progression and poor prognosis in human nasopharyngeal carcinoma. J Pathol 2008, 216:167-175.
• [21]Liu Y, Xie C, Zhang X, Huang D, Zhou X, Tan P, Qi L, Hu G, Tian Y, Qiu Y: Elevated expression of HMGB1 in squamous-cell carcinoma of the head and neck and its clinical significance. Eur J Cancer 2010, 46:3007-3015.
• [22]Jiang W, Wang Z, Li X, Fan X, Duan Y: High-mobility group box 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Pathol Oncol Res 2012, 18:293-298.
• [23]Edge SB, Carducci MA, Compton CC, et al.: AJCC cancer staging manual. 7th edition. Springer, Chicago; 2009:237.
• [24]Peng RQ, Wu XJ, Ding Y, Li CY, Yu XJ, Zhang X, Pan ZZ, Wan DS, Zheng LM, Zeng YX, Zhang XS: Co-expression of nuclear and cytoplasmic HMGB1 is inversely associated with infiltration of CD45RO + T cells and prognosis in patients with stage IIIB colon cancer. BMC Cancer 2010, 10:496. BioMed Central Full Text
• [25]Cheng BQ, Jia CQ, Liu CT, Lu XF, Zhong N, Zhang ZL, Fan W, Li YQ: Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis 2008, 40:446-452.
• [26]Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005, 5:331-342.
• [27]Yang H, Rivera Z, Jube S, Nasu M, Bertino P, Goparaju C, Franzoso G, Lotze MT, Krausz T, Pass HI, Bianchi ME, Carbone M: Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci USA 2010, 107:12611-12616.
• [28]Liang H, Zhong Y, Zhou S, Peng L: Knockdown of RAGE expression inhibits colorectal cancer cell invasion and suppresses angiogenesis in vitro and in vivo. Cancer Lett 2011, 313:91-98.
• [29]Liu Z, Falo LD, You Z: Knockdown of HMGB1 in tumor cells attenuates their ability to induce regulatory T cells and uncovers naturally acquired CD8 T cell-dependent antitumor immunity. J Immunol 2011, 187:118-125.