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Psoriasin (S100A7) associates with integrin β6 subunit and is required for αvβ6-dependent carcinoma cell invasion

Oncogene volume 30, pages 1422–1435 (2011)Cite this article

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Abstract

Expression of the integrin αvβ6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvβ6 composed of wild-type αv and a mutant β6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvβ6-dependent adhesion or migration, are essential for αvβ6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the β6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant β6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous β6 and colocalised with αvβ6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvβ6-dependent adhesion or migration but abrogated αvβ6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the β6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of β6, bound directly to recombinant Psor and inhibited cellular Psor binding to β6; this blocked αvβ6-dependent, but not αvβ6-independent, invasion. These data identify a novel interaction between Psor and β6 and demonstrate that it is required for αvβ6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion.

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References

  • Agrez M, Chen A, Cone RI, Pytela R, Sheppard D . (1994. The alpha v beta 6 integrin promotes proliferation of colon carcinoma cells through a unique region of the beta 6 cytoplasmic domain. J Cell Biol 127: 547–556.

    Article  CAS  Google Scholar 

  • Al-Haddad S, Zhang Z, Leygue E, Snell L, Huang A, Niu Y et al. (1999). Psoriasin (S100A7) expression and invasive breast cancer. Am J Pathol 155: 2057–2066.

    Article  CAS  Google Scholar 

  • Banerjee AG, Bhattacharyya I, Vishwanatha JK . (2005). Identification of genes and molecular pathways involved in the progression of premalignant oral epithelia. Mol Cancer Ther 4: 865–875.

    Article  CAS  Google Scholar 

  • Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H et al. (2005). Transcriptional activation of integrin beta 6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 115: 339–347.

    Article  CAS  Google Scholar 

  • Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF et al. (1995). Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodelling. J Cell Sci 108: 2241–2251.

    CAS  PubMed  Google Scholar 

  • Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R . (1993). Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. J Histochem Cytochem 41: 1521–1527.

    Article  CAS  Google Scholar 

  • Busk M, Pytela R, Sheppard D . (1992). Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. J Biol Chem 267: 5790–5796.

    CAS  PubMed  Google Scholar 

  • Clark RA, Ashcroft GS, Spencer MJ, Larjava H, Ferguson MW . (1996). Re-epithelialization of normal human excisional wounds is associated with a switch from alpha v beta 5 to alpha v beta 6 integrins. Br J Dermatol 135: 46–51.

    Article  CAS  Google Scholar 

  • Elayadi AN, Samli KN, Prudkin L, Liu YH, Bian A, Xie XJ et al. (2007). A peptide selected by biopanning identifies the integrin alpha v beta 6 as a prognostic biomarker for non small cell lung cancer. Cancer Res 67: 5889–5895.

    Article  CAS  Google Scholar 

  • Emberley ED, Murphy LC, Watson PH . (2004). S100A7 and the progression of breast cancer. Breast Cancer Res 6: R308–R315.

    Article  CAS  Google Scholar 

  • Emberley ED, Niu Y, Curtis L, Troup S, Mandal SK, Myers JN et al. (2005). The S100A7-c-jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer. Cancer Res 65: 5696–5702.

    Article  CAS  Google Scholar 

  • Glaser R, Harder J, Lange H, Bartels J, Christophers E, Schroder JM . (2005). Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol 6: 57–64.

    Article  Google Scholar 

  • Haapasalmi K, Zhang K, Tonnesen M, Olerud J, Sheppard D, Salo T et al. (1996). Keratinocytes in human wounds express alpha v beta 6 integrin. J Invest Dermatol 106: 42–48.

    Article  CAS  Google Scholar 

  • Hazelbag S, Kenter GG, Gorter A, Dreef EJ, Koopman LA, Violette SM et al. (2007). Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J Pathol 212: 316–324.

    Article  CAS  Google Scholar 

  • Jiang WG, Watkins G, Douglas-Jones A, Mansel RE . (2004). Psoriasin is aberrantly expressed in human breast cancer and is related to clinical outcomes. Int J Oncol 25: 81–85.

    CAS  PubMed  Google Scholar 

  • Jones J, Sugiyama M, Speight PM, Watt FM . (1996). Restoration of alpha v beta 5 integrin expression in neoplastic keratinocytes results in increased capacity for terminal differentiation and suppression of anchorage-independent growth. Oncogene 12: 119–126.

    CAS  PubMed  Google Scholar 

  • Jones J, Watt FM, Speight PM . (1997). Changes in the expression of alpha v integrins in oral squamous cell carcinomas. J Oral Pathol Med 26: 63–68.

    Article  CAS  Google Scholar 

  • Kesting MR, Sudhoff H, Hasler RJ, Nieberler M, Pautke C, Wolff KD et al. (2009). Psoriasin (S100A7) up-regulation in oral squamous cell carcinoma and its relationto clinicopathologic features. Oral Oncol 45: 731–736.

    Article  CAS  Google Scholar 

  • Krop I, Marz A, Carlsson H, Li X, Bloushtain-Qimron N, Hu M et al. (2005). A putative role for psoriasin in breast tumour progression. Cancer Res 65: 11326–11334.

    Article  CAS  Google Scholar 

  • Kumar CC . (1998). Signaling by integrin receptors. Oncogene 17: 1365–1373.

    Article  CAS  Google Scholar 

  • Larjava H, Haapasalmi K, Salo T, Wiebe C, Uitto VJ . (1996). Keratinocyte integrins in wound healing and chronic inflammation of the human periodontium. Oral Dis 2: 77–86.

    Article  CAS  Google Scholar 

  • León R, Murray JI, Cragg G, Farnell B, West NR, Pace TC et al. (2009). Identification and characterization of binding sites on S100A7, a participant in cancer and inflammation pathways. Biochemistry 48: 10591–10600.

    Article  Google Scholar 

  • Li X, Yang Y, Hu Y, Dang D, Regezi J, Schmidt BL et al. (2003). αvβ6-Fyn signalling promotes oral cancer progression. J Biol Chem 278: 41646–41653.

    Article  CAS  Google Scholar 

  • Liotta LA, Kohn EC . (2001). The microenvironment of the tumour-host interface. Nature 411: 375–379.

    Article  CAS  Google Scholar 

  • Madsen P, Rasmussen HH, Leffers H, Honoré B, Dejgaard K, Olsen E et al. (1992). Molecular cloning, occurrence, and expression of a novel partially secreted protein ‘psoriasin’ that is highly up-regulated in psoriatic skin. J Invest Dermatol 97: 701–712.

    Article  Google Scholar 

  • Morgan MR, Thomas GJ, Russell A, Hart IR, Marshall JF . (2004). The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote tumour cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9. J Biol Chem 279: 26533–26539.

    Article  CAS  Google Scholar 

  • Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J et al. (1999). The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96: 319–328.

    Article  CAS  Google Scholar 

  • Niu J, Dorahy DJ, Gu X, Scott RJ, Draganic B, Ahmed N et al. (2002). Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the beta 6 integrin subunit. Int J Cancer 99: 529–537.

    Article  CAS  Google Scholar 

  • Niu J, Gu X, Ahmed N, Andrews S, Turton J, Bates R et al. (2001). The alpha v beta 6 integrin regulates its own expression with cell crowding: implications for tumour progression. Int J Cancer 92: 40–48.

    Article  CAS  Google Scholar 

  • Nystrom ML, McCulloch D, Weinreb PH, Violette SM, Speight PM, Marshall JF et al. (2006). Cyclooxygenase-2 inhibition suppresses apha v beta 6 integrin-dependent oral squamous carcinoma invasion. Cancer Res 66: 10833–10842.

    Article  CAS  Google Scholar 

  • Nystrom ML, Thomas GJ, Stone M, Mackenzie IC, Hart IR, Marshall JF . (2002). Development of a quantitative method to analyse tumour cell invasion in organotypic culture. J Pathol 205: 468–475.

    Article  Google Scholar 

  • Paruchuri V, Prasad A, McHugh K, Bhat HK, Polyak K, Ganju RK . (2008). S100A7-downregulation inhibits epidermal growth factor-induced signalling in breast cancer cells and blocks osteoclast formation. PLoS One 3: e1741.

    Article  Google Scholar 

  • Petersson S, Bylander A, Yhr M, Enerbäck C . (2007). S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells. BMC Cancer 7: 205.

    Article  Google Scholar 

  • Prieto AL, Edelman GM, Crossin KL . (1993). Multiple integrins mediate cell attachment to cytotactin/tenascin. Proc Natl Acad Sci USA 90: 10154–10158.

    Article  CAS  Google Scholar 

  • Prime SS, Nixon SV, Crane IJ, Stone A, Matthews JB, Maitland NJ et al. (1990). The behaviour of human oral squamous cell carcinoma in culture. J Pathol 160: 259–269.

    Article  CAS  Google Scholar 

  • Ralhan R, DeSouza LV, Malta A, Tripathi SC, Ghanny S, Gupta SD et al. (2008). Discovery and verification of head-and-neck cancer biomarkers by differential protein expression analysis using iTRAQ labelling, multidimensional liquid chromatography, and tandem mass spectrometry. Mol Cell Proteomics 7: 1162–1173.

    Article  CAS  Google Scholar 

  • Ramos DM, But M, Regezi J, Schmidt BL, Atakilit A, Dang D et al. (2002). Expression of integrin beta 6 enhances invasive behaviour in oral squamous cell carcinoma. Matrix Biol 21: 297–307.

    Article  CAS  Google Scholar 

  • Ramsay AG, Keppler MD, Jazayeri M, Thomas GJ, Parsons M, Violette S et al. (2007). HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin alpha v beta 6. Cancer Res 67: 5275–5284.

    Article  CAS  Google Scholar 

  • Regezi JA, Ramos DM, Pytela R, Dekker NP, Jordan RC . (2002). Tenascin and beta 6 integrin are overexpressed in floor of mouth in situ carcinomas and invasive squamous cell carcinoma. Oral Oncol 38: 332–336.

    Article  CAS  Google Scholar 

  • Reska AA, Hayashi Y, Horwitz AF . (1992). Identification of amino acid sequences in the integrin beta 1 cytoplasmic domain implicated in cytoskeletal association. J Cell Biol 117: 1321–1330.

    Article  Google Scholar 

  • Ruse M, Broome AM, Eckert RL . (2003). S100A7 (psoriasin) interacts with epidermal fatty acid binding protein and localizes in focal adhesion-like structures in cultured keratinocytes. J Invest Dermatol 121: 132–141.

    Article  CAS  Google Scholar 

  • Sugiyama M, Speight PM, Prime SS, Watt FM . (1993). Comparison of integrin expression and terminal differentiation capacity in cell lines derived from oral squamous cell carcinomas. Carcinogenesis 14: 2171–2176.

    Article  CAS  Google Scholar 

  • Thomas GJ, Hart IR, Speight PM, Marshall JF . (2002). Binding of TGF-beta 1 latency-associated peptide (LAP) to alpha(v) beta 6 integrin modulates behaviour of squamous carcinoma cells. Br J Cancer 87: 859–867.

    Article  CAS  Google Scholar 

  • Thomas GJ, Lewis MP, Hart IR, Marshall JF, Speight PM . (2001a). Alpha v beta 6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase 9. Int J Cancer 92: 641–650.

    Article  CAS  Google Scholar 

  • Thomas GJ, Lewis MP, Whawell SA, Russell A, Sheppard D, Hart IR et al. (2001b). Expression of the alpha v beta 6 integrin promotes migration and invasion in squamous carcinoma cells. J Invest Dermatol 117: 67–73.

    Article  CAS  Google Scholar 

  • Thomas GJ, Nystrom ML, Marshall JF . (2006). Alpha v beta 6 integrin in wound healing and cancer of the oral cavity. J Oral Pathol Med 35: 1–10.

    Article  CAS  Google Scholar 

  • Thomas GJ, Poomsawat S, Lewis MP, Hart IR, Speight PM, Marshall JF . (2001c). Alpha v beta 6 integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. J Invest Dermatol 116: 898–904.

    Article  CAS  Google Scholar 

  • Wang J, Barnes RO, West NR, Olson M, Chu JE, Watson PH . (2008). Jab1 is a target of EGFR signalling in ERalpha-negative breast cancer. Breast Cancer Res 10: R51.

    Article  Google Scholar 

  • Weinacker A, Chen A, Agrez M, Cone RI, Nishimura S, Wayner E et al. (1994). Role of integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor. J Biol Chem 269: 6940–6948.

    CAS  PubMed  Google Scholar 

  • Wolf R, Howard OMZ, Dong H-F, Voscopoulos C, Boeshans K, Winston J et al. (2008). Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15. J Immunol 181: 1499–1506.

    Article  CAS  Google Scholar 

  • Zhou G, Xie TX, Zhao M, Jasser SA, Younes MN, Sano D et al. (2008). Reciprocal negative regulation between S100A7/psoriasin and beta-catenin signalling plays an important role in tumour progression of squamous cell carcinoma of oral cavity. Oncogene 27: 3527–3538.

    Article  CAS  Google Scholar 

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Author notes

  1. M R Morgan

    Present address: 4Current address: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Michael Smith Building, Manchester M13 9PT, UK,

  2. M R Morgan & M Jazayeri

    Present address: 5Current address: University of Southampton, School of Medicine, Cancer Sciences Division, Somers Building, Tremona Road, Southampton S016 6YD, UK,

  3. G J Thomas: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Tumour Biology, The London School of Medicine and Dentistry, John Vane Science Centre, London, UK

    M R Morgan, M Jazayeri, A G Ramsay, G J Thomas, I R Hart & J F Marshall

  2. Centre for Medical Oncology, Institute of Cancer, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, London, UK

    A G Ramsay

  3. Department of Biochemistry and Microbiology, Victoria, British Columbia, Canada

    M J Boulanger

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Correspondence to J F Marshall.

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Morgan, M., Jazayeri, M., Ramsay, A. et al. Psoriasin (S100A7) associates with integrin β6 subunit and is required for αvβ6-dependent carcinoma cell invasion. Oncogene 30, 1422–1435 (2011). https://doi.org/10.1038/onc.2010.535

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