Abstract
The inflammatory environment and existence of cancer stem cells are critical for progression and intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the prognostic significance of combining high mobility group box 1 (HMGB1) expression and hepatic progenitor marker OV6 in hepatocellular carcinoma. Expression of HMGB1 and OV6 was evaluated using immunohistochemistry profiling in tissue microarrays containing samples from 208 HCC patients. Invasive clinical or pathological factors were found in patients with high expression of HMGB1 or OV6. Higher HMGB1 was associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (85.5% vs. 62.4%, P<0.001). We also found that more OV6 positive staining was correlated with poor prognosis of HCC patients (P<0.001). Notably, expression of HMGB1 was positively correlated with OV6 in density (R2=0.032, P<0.001) and reversely related to HCC outcomes. Abnormal expression of HMGB1 in combination with positive staining of OV6 displayed poorer prognostic performance than single biomarker alone (area under curve (AUC) survival=0.696). Therefore, HMGB1 and OV6 positive staining are promising prognostic parameters for HCC, and we propose that HMGB1 and OV6 may cooperate with each other and predict poor prognosis of HCC.
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Allegra, C.J., Jessup, J.M., Somerfield, M.R., Hamilton, S.R., Hammond, E.H., Hayes, D.F., McAllister, P.K., Morton, R.F., and Schilsky, R.L. (2009). American Society of Clinical Oncology Provisional Clinical Opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27, 2091–2096.
Aravalli, R.N., Steer, C.J., and Cressman, E.N.K. (2008). Molecular mechanisms of hepatocellular carcinoma. Hepatology 48, 2047–2063.
Bassi, R., Giussani, P., Anelli, V., Colleoni, T., Pedrazzi, M., Patrone, M., Viani, P., Sparatore, B., Melloni, E., and Riboni, L. (2008). HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. J Neurooncol 87, 23–33.
Brezniceanu, M.L., Volp, K., Bosser, S., Solbach, C., Lichter, P., Joos, S., and Zornig, M. (2003). HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. FASEB J 17, 1295–1297.
Chen, S., Dong, Z., Yang, P., Wang, X., Jin, G., Yu, H., Chen, L., Li, L., Tang, L., Bai, S., Yan, H., Shen, F., Cong, W., Wen, W., and Wang, H. (2017). Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis. Cancer Lett 394, 22–32.
Dukic-Stefanovic, S., Gasic-Milenkovic, J., Deuther-Conrad, W., and Münch, G. (2003). Signal transduction pathways in mouse microglia N-11 cells activated by advanced glycation endproducts (AGEs). J Neurochem 87, 44–55.
Ellerman, J.E., Brown, C.K., de Vera, M., Zeh, H.J., Billiar, T., Rubartelli, A., and Lotze, M.T. (2007). Masquerader: high mobility group Box-1 and cancer. Clin Cancer Res 13, 2836–2848.
Gerlinger, M., Rowan, A.J., Horswell, S., Math, M., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N.Q., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C.R., Nohadani, M., Eklund, A. C., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P.A., and Swanton, C. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366, 883–892.
Hofmann, M.A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P., Neurath, M.F., Slattery, T., Beach, D., McClary, J., Nagashima, M., Morser, J., Stern, D., and Schmidt, A.M. (1999). RAGE mediates a novel proinflammatory axis. Cell 97, 889–901.
Hudson, B.I., Kalea, A.Z., Del Mar Arriero, M., Harja, E., Boulanger, E., D’Agati, V., and Schmidt, A.M. (2008). Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283, 34457–34468.
Huttunen, H.J., Kuja-Panula, J., Sorci, G., Agneletti, A.L., Donato, R., and Rauvala, H. (2000). Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 275, 40096–40105.
Jain, K.K. (2007). Cancer biomarkers: current issues and future directions. Curr Opin Mol Ther 9, 563–571.
Jordan, C.T., Guzman, M.L., and Noble, M. (2006). Cancer stem cells. N Engl J Med 355, 1253–1261.
Kim, J.Y., Park, H.K., Yoon, J.S., Kim, S.J., Kim, E.S., Ahn, K.S., Kim, D. S., Yoon, S.S., Kim, B.K., and Lee, Y.Y. (2008). Advanced glycation end product (AGE)-induced proliferation of HEL cells via receptor for AGE-related signal pathways. Int J Oncol 33, 493–501.
Li, X.F., Chen, C., Xiang, D.M., Qu, L., Sun, W., Lu, X.Y., Zhou, T.F., Chen, S.Z., Ning, B.F., Cheng, Z., Xia, M.Y., Shen, W.F., Yang, W., Wen, W., Lee, T.K.W., Cong, W.M., Wang, H.Y., and Ding, J. (2017). Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology in press doi: 10.1002/hep.29372.
Ling, S., Hu, Z., Yang, Z., Yang, F., Li, Y., Lin, P., Chen, K., Dong, L., Cao, L., Tao, Y., Hao, L., Chen, Q., Gong, Q., Wu, D., Li, W., Zhao, W., Tian, X., Hao, C., Hungate, E.A., Catenacci, D.V.T., Hudson, R.R., Li, W.H., Lu, X., and Wu, C.I. (2015). Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci USA 112, e6496–E6505.
Llovet, J.M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., and Gores, G. (2016). Hepatocellular carcinoma. Nat Rev Dis Primers 2, 16018.
Magna, M., and Pisetsky, D.S. (2014). The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med 20, 1–146.
Medema, J.P. (2013). Cancer stem cells: the challenges ahead. Nat Cell Biol 15, 338–344.
Murray, C.J.L., Vos, T., Lozano, R., Naghavi, M., Flaxman, A.D., Michaud, C., Ezzati, M., Shibuya, K., Salomon, J.A., Abdalla, S., Aboyans, V., Abraham, J., Ackerman, I., Aggarwal, R., Ahn, S.Y., Ali, M.K., AlMazroa, M.A., Alvarado, M., Anderson, H.R., Anderson, L.M., Andrews, K.G., Atkinson, C., Baddour, L.M., Bahalim, A.N., Barker-Collo, S., Barrero, L.H., Bartels, D.H., Basáñez, M.G., Baxter, A., Bell, M.L., Benjamin, E.J., Bennett, D., Bernabé, E., Bhalla, K., Bhandari, B., Bikbov, B., Abdulhak, A.B., Birbeck, G., Black, J.A., Blencowe, H., Blore, J.D., Blyth, F., Bolliger, I., Bonaventure, A., Boufous, S., Bourne, R., Boussinesq, M., Braithwaite, T., Brayne, C., Bridgett, L., Brooker, S., Brooks, P., Brugha, T.S., Bryan-Hancock, C., Bucello, C., Buchbinder, R., Buckle, G., Budke, C.M., Burch, M., Burney, P., Burstein, R., Calabria, B., Campbell, B., Canter, C.E., Carabin, H., Carapetis, J., Carmona, L., Cella, C., Charlson, F., Chen, H., Cheng, A.T. A., Chou, D., Chugh, S.S., Coffeng, L.E., Colan, S.D., Colquhoun, S., Colson, K.E., Condon, J., Connor, M.D., Cooper, L.T., Corriere, M., Cortinovis, M., de Vaccaro, K.C., Couser, W., Cowie, B.C., Criqui, M. H., Cross, M., Dabhadkar, K.C., Dahiya, M., Dahodwala, N., Damsere-Derry, J., Danaei, G., Davis, A., Leo, D.D., Degenhardt, L., Dellavalle, R., Delossantos, A., Denenberg, J., Derrett, S., Des Jarlais, D.C., Dharmaratne, S.D., Dherani, M., Diaz-Torne, C., Dolk, H., Dorsey, E.R., Driscoll, T., Duber, H., Ebel, B., Edmond, K., Elbaz, A., Ali, S.E., Erskine, H., Erwin, P.J., Espindola, P., Ewoigbokhan, S.E., Farzadfar, F., Feigin, V., Felson, D.T., Ferrari, A., Ferri, C.P., Fèvre, E.M., Finucane, M.M., Flaxman, S., Flood, L., Foreman, K., Forouzanfar, M.H., Fowkes, F.G.R., Fransen, M., Freeman, M.K., Gabbe, B.J., Gabriel, S. E., Gakidou, E., Ganatra, H.A., Garcia, B., Gaspari, F., Gillum, R.F., Gmel, G., Gonzalez-Medina, D., Gosselin, R., Grainger, R., Grant, B., Groeger, J., Guillemin, F., Gunnell, D., Gupta, R., Haagsma, J., Hagan, H., Halasa, Y.A., Hall, W., Haring, D., Haro, J.M., Harrison, J.E., Havmoeller, R., Hay, R.J., Higashi, H., Hill, C., Hoen, B., Hoffman, H., Hotez, P.J., Hoy, D., Huang, J.J., Ibeanusi, S.E., Jacobsen, K.H., James, S.L., Jarvis, D., Jasrasaria, R., Jayaraman, S., Johns, N., Jonas, J.B., Karthikeyan, G., Kassebaum, N., Kawakami, N., Keren, A., Khoo, J.P., King, C.H., Knowlton, L.M., Kobusingye, O., Koranteng, A., Krishnamurthi, R., Laden, F., Lalloo, R., Laslett, L.L., Lathlean, T., Leasher, J. L., Lee, Y.Y., Leigh, J., Levinson, D., Lim, S.S., Limb, E., Lin, J.K., Lipnick, M., Lipshultz, S.E., Liu, W., Loane, M., Ohno, S.L., Lyons, R., Mabweijano, J., MacIntyre, M.F., Malekzadeh, R., Mallinger, L., Manivannan, S., Marcenes, W., March, L., Margolis, D.J., Marks, G.B., Marks, R., Matsumori, A., Matzopoulos, R., Mayosi, B.M., McAnulty, J.H., McDermott, M.M., McGill, N., McGrath, J., Medina-Mora, M.E., Meltzer, M., Memish, Z.A., Mensah, G.A., Merriman, T.R., Meyer, A. C., Miglioli, V., Miller, M., Miller, T.R., Mitchell, P.B., Mock, C., Mocumbi, A.O., Moffitt, T.E., Mokdad, A.A., Monasta, L., Montico, M., Moradi-Lakeh, M., Moran, A., Morawska, L., Mori, R., Murdoch, M.E., Mwaniki, M.K., Naidoo, K., Nair, M.N., Naldi, L., Narayan, K.M.V., Nelson, P.K., Nelson, R.G., Nevitt, M.C., Newton, C.R., Nolte, S., Norman, P., Norman, R., O’Donnell, M., O’Hanlon, S., Olives, C., Omer, S.B., Ortblad, K., Osborne, R., Ozgediz, D., Page, A., Pahari, B., Pandian, J.D., Rivero, A.P., Patten, S.B., Pearce, N., Padilla, R.P., Perez-Ruiz, F., Perico, N., Pesudovs, K., Phillips, D., Phillips, M.R., Pierce, K., Pion, S., Polanczyk, G.V., Polinder, S., Pope Iii, C.A., Popova, S., Porrini, E., Pourmalek, F., Prince, M., Pullan, R.L., Ramaiah, K.D., Ranganathan, D., Razavi, H., Regan, M., Rehm, J.T., Rein, D.B., Remuzzi, G., Richardson, K., Rivara, F.P., Roberts, T., Robinson, C., De Leòn, F.R., Ronfani, L., Room, R., Rosenfeld, L.C., Rushton, L., Sacco, R.L., Saha, S., Sampson, U., Sanchez-Riera, L., Sanman, E., Schwebel, D.C., Scott, J.G., Segui-Gomez, M., Shahraz, S., Shepard, D.S., Shin, H., Shivakoti, R., Silberberg, D., Singh, D., Singh, G.M., Singh, J.A., Singleton, J., Sleet, D.A., Sliwa, K., Smith, E., Smith, J.L., Stapelberg, N.J., Steer, A., Steiner, T., Stolk, W.A., Stovner, L.J., Sudfeld, C., Syed, S., Tamburlini, G., Tavakkoli, M., Taylor, H.R., Taylor, J.A., Taylor, W. J., Thomas, B., Thomson, W.M., Thurston, G.D., Tleyjeh, I.M., Tonelli, M., Towbin, J.A., Truelsen, T., Tsilimbaris, M.K., Ubeda, C., Undurraga, E.A., van der Werf, M.J., van Os, J., Vavilala, M.S., Venketasubramanian, N., Wang, M., Wang, W., Watt, K., Weatherall, D.J., Weinstock, M.A., Weintraub, R., Weisskopf, M.G., Weissman, M.M., White, R.A., Whiteford, H., Wiebe, N., Wiersma, S.T., Wilkinson, J.D., Williams, H.C., Williams, S.R., Witt, E., Wolfe, F., Woolf, A.D., Wulf, S., Yeh, P.H., Zaidi, A.K., Zheng, Z.J., Zonies, D., and Lopez, A.D. (2012). Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2197–2223.
Nathan, H., Schulick, R.D., Choti, M.A., and Pawlik, T.M. (2009). Predictors of survival after resection of early hepatocellular carcinoma. Ann Surgery 249, 799–805.
Paik, S., Shak, S., Tang, G., Kim, C., Baker, J., Cronin, M., Baehner, F.L., Walker, M.G., Watson, D., Park, T., Hiller, W., Fisher, E.R., Wickerham, D.L., Bryant, J., and Wolmark, N. (2004). A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351, 2817–2826.
Palumbo, R., De Marchis, F., Pusterla, T., Conti, A., Alessio, M., and Bianchi, M.E. (2009). Src family kinases are necessary for cell migration induced by extracellular HMGB1. J Leukocyte Biol 86, 617–623.
Reddy, M.A., Li, S.L., Sahar, S., Kim, Y.S., Xu, Z.G., Lanting, L., and Natarajan, R. (2006). Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells. J Biol Chem 281, 13685–13693.
Roskams, T. (2006). Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25, 3818–3822.
Schiraldi, M., Raucci, A., Muñoz, L.M., Livoti, E., Celona, B., Venereau, E., Apuzzo, T., De Marchis, F., Pedotti, M., Bachi, A., Thelen, M., Varani, L., Mellado, M., Proudfoot, A., Bianchi, M.E., and Uguccioni, M. (2012). HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med 209, 551–563.
Sherman, M. (2008). Recurrence of hepatocellular carcinoma. N Engl J Med 359, 2045–2047.
Shigdar, S., Li, Y., Bhattacharya, S., O’Connor, M., Pu, C., Lin, J., Wang, T., Xiang, D., Kong, L., Wei, M.Q., Zhu, Y., Zhou, S., and Duan, W. (2014). Inflammation and cancer stem cells. Cancer Lett 345, 271–278.
Sia, D., Villanueva, A., Friedman, S.L., and Llovet, J.M. (2017). Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761.
Sims, G.P., Rowe, D.C., Rietdijk, S.T., Herbst, R., and Coyle, A.J. (2010). HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 28, 367–388.
Sparvero, L.J., Asafu-Adjei, D., Kang, R., Tang, D., Amin, N., Im, J., Rutledge, R., Lin, B., Amoscato, A.A., Zeh, H.J., and Lotze, M.T. (2009). RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med 7, 17.
Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., and Jemal, A. (2015). Global cancer statistics, 2012. CA Cancer J Clin 65, 87–108.
Touré, F., Zahm, J.M., Garnotel, R., Lambert, E., Bonnet, N., Schmidt, A. M., Vitry, F., Chanard, J., Gillery, P., and Rieu, P. (2008). Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix. Biochem J 416, 255–261.
Tsung, A., Tohme, S., and Billiar, T.R. (2014). High-mobility group box-1 in sterile inflammation. J Intern Med 276, 425–443.
Villanueva, A., Toffanin, S., and Llovet, J.M. (2008). Linking molecular classification of hepatocellular carcinoma and personalized medicine: preliminary steps. Curr Opin Oncol 20, 444–453.
Yamashita, T., and Wang, X.W. (2013). Cancer stem cells in the development of liver cancer. J Clin Invest 123, 1911–1918.
Yan, W., Chang, Y., Liang, X., Cardinal, J.S., Huang, H., Thorne, S.H., Monga, S.P.S., Geller, D.A., Lotze, M.T., and Tsung, A. (2012). Highmobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 55, 1863–1875.
Yang, W., Wang, C., Lin, Y., Liu, Q., Yu, L., Tang, L., Yan, H.X., Fu, J., Chen, Y., Zhang, H.L., Tang, L., Zheng, L.Y., He, Y.Q., Li, Y.Q., Wu, F. Q., Zou, S.S., Li, Z., Wu, M.C., Feng, G.S., and Wang, H.Y. (2012). OV6+ tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma. J Hepatol 57, 613–620.
Yang, W., Yan, H.X., Chen, L., Liu, Q., He, Y.Q., Yu, L.X., Zhang, S.H., Huang, D.D., Tang, L., Kong, X.N., Chen, C., Liu, S.Q., Wu, M.C., and Wang, H.Y. (2008). Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68, 4287–4295.
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This work was supported by the National Natural Science Foundation of China (81370061, 81521091, 81572896, 81370137, 81722034) and the National Science and Technology Key Projects (2017ZX10203205, 2017ZX10302202).
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Zhu, J., Yu, H., Chen, S. et al. Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma. Sci. China Life Sci. 61, 912–923 (2018). https://doi.org/10.1007/s11427-017-9188-x
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DOI: https://doi.org/10.1007/s11427-017-9188-x