High S100A8 and S100A12 protein expression is a favorable prognostic factor for survival of oropharyngeal squamous cell carcinoma
Sonja Funk
Department of Otolaryngology, University Hospital Essen, Essen, Germany
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorRegina Mark
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorPilar Bayo
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorChrista Flechtenmacher
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorNiels Grabe
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany
Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
Search for more papers by this authorPeter Angel
Division Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter K. Plinkert
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Jochen Hess
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Correspondence to: Jochen Hess, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, Tel.: +49(0)6221-56-39505, Fax: +49(0)6221-56-4604, E-mail: [email protected]Search for more papers by this authorSonja Funk
Department of Otolaryngology, University Hospital Essen, Essen, Germany
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorRegina Mark
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorPilar Bayo
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorChrista Flechtenmacher
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorNiels Grabe
Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany
Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
Search for more papers by this authorPeter Angel
Division Signal Transduction and Growth Control, DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Heidelberg, Germany
Search for more papers by this authorPeter K. Plinkert
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Jochen Hess
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center Heidelberg, Heidelberg, Germany
Correspondence to: Jochen Hess, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, Tel.: +49(0)6221-56-39505, Fax: +49(0)6221-56-4604, E-mail: [email protected]Search for more papers by this authorAbstract
S100/calgranulins (S100A8, S100A9 and S100A12) are key players of innate immune function and elevated levels are a characteristic feature of acute and chronic inflammation, and inflammation-associated carcinogenesis. However, reduced S100A8 and S100A9 expression has been detected for squamous cell carcinoma, including the head and neck region (HNSCC), which originate from mucosal epithelia with abundant expression of both proteins under physiological conditions. In contrast to S100A8 and S100A9, only sparse information is available for S100A12 and a comparative study of all three S100/calgranulins in HNSCC is still missing. We analyzed S100/calgranulin protein levels in a retrospective patient cohort (n = 131) of oropharyngeal squamous cell carcinoma (OPSCC) by immunohistochemical staining of tissue microarrays. Common characteristics of all three S100/calgranulins were: (i) abundant expression in supra-basal keratinocytes of normal mucosa with predominant nuclear staining, (ii) low expression in 30.4–51.9% of primary OPSCCs and (iii) variable accumulation of S100/calgranulin-positive immune cells in the tumor stroma. These features were associated with histopathological characteristics, such as tumor grade, lymph node metastasis and tumor stage. Furthermore, univariate and multivariate analysis revealed worse overall survival of OPSCC patients with simultaneous reduction of S100A8 and S100A12 expression, while expression of S100A9 or presence of the S100A8/S100A9 heterodimer had no impact, suggesting distinct regulation and function of individual S100/calgranulins in the pathogenesis of HNSCCs.
Abstract
What's new?
Inflammation can alter the expression of specific proteins, and in the context of head and neck squamous cell carcinoma (HNSCC), which involves a high degree of inflammation, those changes may be of diagnostic or prognostic significance. Here, reduced expression of calcium-binding S100/calgranulin proteins was found to be a common feature of oropharyngeal SCC. Moreover, simultaneous low protein expression of S100A8 and S100A12 in tumor cells was an independent risk factor for unfavorable overall survival. The regulation and function of S100/calgranulins likely is context-dependent, with differences between mucosal and squamous epithelia.
Supporting Information
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References
- 1 Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11: 9–22.
- 2 Rothenberg SM, Ellisen LW. The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest 2012; 122: 1951–7.
- 3
Kostareli E,
Holzinger D,
Hess J. New concepts for translational head and neck oncology: lessons from HPV-related oropharyngeal squamous cell carcinomas. Front Oncol 2012; 2: 1–10.
10.3389/fonc.2012.00036 Google Scholar
- 4 Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24–35.
- 5 Pries R, Nitsch S, Wollenberg B. Role of cytokines in head and neck squamous cell carcinoma. Expert Rev Anticancer Ther 2006; 6: 1195–203.
- 6 Wang F, Arun P, Friedman J, et al. Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol 2009; 9: 389–95.
- 7 Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature 2008; 454: 436–44.
- 8 Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–22.
- 9 Hiratsuka S, Watanabe A, Aburatani H, et al. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 2006; 8: 1369–75.
- 10 Hiratsuka S, Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 2008; 10: 1349–55.
- 11 Donato R, Cannon BR, Sorci G, et al. Functions of S100 proteins. Curr Mol Med 2013; 13: 24–57.
- 12 Goyette J, Geczy CL. Inflammation-associated S100 proteins: new mechanisms that regulate function. Amino Acids 2011; 41: 821–42.
- 13 Perera C, McNeil HP, Geczy CL. S100 Calgranulins in inflammatory arthritis. Immunol Cell Biol 2010; 88: 41–9.
- 14 Foell D, Wittkowski H, Vogl T, et al. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007; 81: 28–37.
- 15 Gebhardt C, Nemeth J, Angel P, et al. S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol 2006; 72: 1622–31.
- 16 Rammes A, Roth J, Goebeler M, et al. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem 1997; 272: 9496–502.
- 17 Ehrchen JM, Sunderkotter C, Foell D, et al. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 2009; 86: 557–66.
- 18 Riehl A, Nemeth J, Angel P, et al. The receptor RAGE: bridging inflammation and cancer. Cell Commun Signal 2009; 7: 12.
- 19 Sims GP, Rowe DC, Rietdijk ST, et al. HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010; 28: 367–88.
- 20 Srikrishna G. S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun 2012; 4: 31–40.
- 21 Ichikawa M, Williams R, Wang L, et al. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 2011; 9: 133–48.
- 22 Nemeth J, Stein I, Haag D, et al. S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis. Hepatology 2009; 50: 1251–62.
- 23 Cheng P, Corzo CA, Luetteke N, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008; 205: 2235–49.
- 24 Roesch Ely M, Nees M, Karsai S, et al. Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma. Eur J Cell Biol 2005; 84: 431–44.
- 25 Gonzalez HE, Gujrati M, Frederick M, et al. Identification of 9 genes differentially expressed in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2003; 129: 754–9.
- 26 Koffler J, Holzinger D, Sanhueza GA, et al. Submaxillary gland androgen-regulated protein 3A expression is an unfavorable risk factor for the survival of oropharyngeal squamous cell carcinoma patients after surgery. Eur Arch Otorhinolaryngol 2013; 270: 1493–500.
- 27 Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 2005; 437: 369–75.
- 28 Melle C, Ernst G, Schimmel B, et al. A technical triade for proteomic identification and characterization of cancer biomarkers. Cancer Res 2004; 64: 4099–104.
- 29 Fung LF, Lo AK, Yuen PW, et al. Differential gene expression in nasopharyngeal carcinoma cells. Life Sci 2000; 67: 923–36.
- 30 Luo A, Kong J, Hu G, et al. Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray. Oncogene 2004; 23: 1291–9.
- 31 Ji J, Zhao L, Wang X, et al. Differential expression of S100 gene family in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 2004; 130: 480–6.
- 32 Wang J, Cai Y, Xu H, et al. Expression of MRP14 gene is frequently down-regulated in Chinese human esophageal cancer. Cell Res 2004; 14: 46–53.
- 33 Kong JP, Ding F, Zhou CN, et al. Loss of myeloid-related proteins 8 and myeloid-related proteins 14 expression in human esophageal squamous cell carcinoma correlates with poor differentiation. World J Gastroenterol 2004; 10: 1093–7.
- 34 Tugizov S, Berline J, Herrera R, et al. Inhibition of human papillomavirus type 16 E7 phosphorylation by the S100 MRP-8/14 protein complex. J Virol 2005; 79: 1099–112.
- 35 Zhu H, Wu TC, Chen WQ, et al. Roles of galectin-7 and S100A9 in cervical squamous carcinoma: clinicopathological and in vitro evidence. Int J Cancer 2013; 132: 1051–9.
- 36 Voss A, Bode G, Sopalla C, et al. Expression of S100A8/A9 in HaCaT keratinocytes alters the rate of cell proliferation and differentiation. FEBS Lett 2011; 585: 440–6.
- 37 Nukui T, Ehama R, Sakaguchi M, et al. S100A8/A9, a key mediator for positive feedback growth stimulation of normal human keratinocytes. J Cell Biochem 2008; 104: 453–64.
- 38 Ghavami S, Rashedi I, Dattilo BM, et al. S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 2008; 83: 1484–92.
- 39 Mark R, Bermejo JL, Bierhaus A, et al. The receptor for advanced glycation end products is dispensable in a mouse model of oral and esophageal carcinogenesis. Histol Histopathol 2013; 28: 1585–94.
- 40 Schonthaler HB, Guinea-Viniegra J, Wculek SK, et al. S100A8-S100A9 protein complex mediates psoriasis by regulating the expression of complement factor C3. Immunity 2013; 39: 1171–81.
- 41 Grimbaldeston MA, Geczy CL, Tedla N, et al. S100A8 induction in keratinocytes by ultraviolet A irradiation is dependent on reactive oxygen intermediates. J Invest Dermatol 2003; 121: 1168–74.
- 42 Khammanivong A, Wang C, Sorenson BS, et al. S100A8/A9 (Calprotectin) negatively regulates G2/M cell cycle progression and growth of squamous cell carcinoma. PloS One 2013; 8: e69395.
- 43 Champaiboon C, Sappington KJ, Guenther BD, et al. Calprotectin S100A9 calcium-binding loops I and II are essential for keratinocyte resistance to bacterial invasion. J Biol Chem 2009; 284: 7078–90.
- 44 Hermani A, De Servi B, Medunjanin S, et al. S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells. Exp Cell Res 2006; 312: 184–97.
- 45 Ravasi T, Hsu K, Goyette J, et al. Probing the S100 protein family through genomic and functional analysis. Genomics 2004; 84: 10–22.
- 46 Passey RJ, Williams E, Lichanska AM, et al. A null mutation in the inflammation-associated S100 protein S100A8 causes early resorption of the mouse embryo. J Immunol 1999; 163: 2209–16.
- 47 Hobbs JA, May R, Tanousis K, et al. Myeloid cell function in MRP-14 (S100A9) null mice. Mol Cell Biol 2003; 23: 2564–76.
- 48 Manitz MP, Horst B, Seeliger S, et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol Cell Biol 2003; 23: 1034–43.
- 49 Mark R. S100-RAGE signaling in the pathogenesis of head and neck squamous cell carcinoma, Department of Otolaryngology, Head and Neck Surgery, vol. PhD: Ruperto-Carola University of Heidelberg, Germany, 2013.
- 50 McNeill E, Hogg N. S100A9 has a protective role in inflammation-induced skin carcinogenesis. Int J Cancer 2014; 135: 798–808.
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