Skip to main content

Advertisement

SpringerLink
Log in

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660. doi:10.1038/nm0603-653

    Article  PubMed  CAS  Google Scholar 

  2. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410. doi:10.1038/nrc1093

    Article  PubMed  CAS  Google Scholar 

  3. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18(1):4–25

    Article  PubMed  CAS  Google Scholar 

  4. Liu Y, Cox SR, Morita T, Kourembanas S (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 77(3):638–643

    Article  PubMed  CAS  Google Scholar 

  5. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95(20):11715–11720

    Article  PubMed  CAS  Google Scholar 

  6. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP (1996) Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56(9):2013–2016

    PubMed  CAS  Google Scholar 

  7. Lee AH, Dublin EA, Bobrow LG, Poulsom R (1998) Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J Pathol 185(4):394–401. doi:10.1002/(SICI)1096-9896(199808)185:4<394:AID-PATH117>3.0.CO;2-S

    Article  PubMed  CAS  Google Scholar 

  8. Emberley ED, Murphy LC, Watson PH (2004) S100A7 and the progression of breast cancer. Breast Cancer Res 6(4):153–159. doi:10.1186/bcr816

    Article  PubMed  CAS  Google Scholar 

  9. Enerback C, Porter DA, Seth P, Sgroi D, Gaudet J, Weremowicz S, Morton CC, Schnitt S, Pitts RL, Stampl J, Barnhart K, Polyak K (2002) Psoriasin expression in mammary epithelial cells in vitro and in vivo. Cancer Res 62(1):43–47

    PubMed  CAS  Google Scholar 

  10. Emberley ED, Niu Y, Njue C, Kliewer EV, Murphy LC, Watson PH (2003) Psoriasin (S100A7) expression is associated with poor outcome in estrogen receptor-negative invasive breast cancer. Clin Cancer Res 9(7):2627–2631

    PubMed  CAS  Google Scholar 

  11. Watson PH, Leygue ER, Murphy LC (1998) Psoriasin (S100A7). Int J Biochem Cell Biol 30(5):567–571. doi:S1357-2725(97)00066-6

    Article  PubMed  CAS  Google Scholar 

  12. Petersson S, Shubbar E, Yhr M, Kovacs A, Enerback C (2011) Loss of ICAM-1 signaling induces psoriasin (S100A7) and MUC1 in mammary epithelial cells. Breast Cancer Res Treat 125(1):13–25. doi:10.1007/s10549-010-0820-4

    Article  PubMed  CAS  Google Scholar 

  13. Carlsson H, Yhr M, Petersson S, Collins N, Polyak K, Enerback C (2005) Psoriasin (S100A7) and calgranulin-B (S100A9) induction is dependent on reactive oxygen species and is downregulated by Bcl-2 and antioxidants. Cancer Biol Ther 4(9):998–1005

    Article  PubMed  CAS  Google Scholar 

  14. Krop I, Marz A, Carlsson H, Li X, Bloushtain-Qimron N, Hu M, Gelman R, Sabel MS, Schnitt S, Ramaswamy S, Kleer CG, Enerback C, Polyak K (2005) A putative role for psoriasin in breast tumor progression. Cancer Res 65(24):11326–11334. doi:10.1158/0008-5472.CAN-05-1523

    Article  PubMed  CAS  Google Scholar 

  15. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC (2003) Telomerase maintains telomere structure in normal human cells. Cell 114(2):241–253

    Article  PubMed  CAS  Google Scholar 

  16. Skliris GP, Lewis A, Emberley E, Peng B, Weebadda WK, Kemp A, Davie JR, Shiu RP, Watson PH, Murphy LC (2007) Estrogen receptor-beta regulates psoriasin (S100A7) in human breast cancer. Breast Cancer Res Treat 104(1):75–85. doi:10.1007/s10549-006-9390-x

    Article  PubMed  CAS  Google Scholar 

  17. Sato T, Wu X, Shimogaito N, Takino J, Yamagishi S, Takeuchi M (2009) Effects of high-AGE beverage on RAGE and VEGF expressions in the liver and kidneys. Eur J Nutr 48(1):6–11. doi:10.1007/s00394-008-0753-4

    Article  PubMed  CAS  Google Scholar 

  18. Doroudi R, Andersson M, Svensson PA, Ekman M, Jern S, Karlsson L (2005) Methodological studies of multiple reference genes as endogenous controls in vascular gene expression studies. Endothelium 12(5–6):215–223. doi:10.1080/10623320500476377

    Article  PubMed  CAS  Google Scholar 

  19. Petersson S, Bylander A, Yhr M, Enerback 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. doi:10.1186/1471-2407-7-205

    Article  PubMed  Google Scholar 

  20. Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF (2008) Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer’s disease. J Alzheimers Dis 14(2):225–234

    PubMed  CAS  Google Scholar 

  21. Greten J, Kreis I, Wiesel K, Stier E, Schmidt AM, Stern DM, Ritz E, Waldherr R, Nawroth PP (1996) Receptors for advance glycation end-products (AGE) - expression by endothelial cells in non-diabetic uraemic patients. Nephrol Dial Transplant 11(5):786–790

    Article  PubMed  CAS  Google Scholar 

  22. Wolf R, Howard OM, Dong HF, Voscopoulos C, Boeshans K, Winston J, Divi R, Gunsior M, Goldsmith P, Ahvazi B, Chavakis T, Oppenheim JJ, Yuspa SH (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(2):1499–1506

    PubMed  CAS  Google Scholar 

  23. Hsieh HL, Schafer BW, Sasaki N, Heizmann CW (2003) Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays. Biochem Biophys Res Commun 307(2):375–381

    Article  PubMed  CAS  Google Scholar 

  24. Luczak K, Balcerczyk A, Soszynski M, Bartosz G (2004) Low concentration of oxidant and nitric oxide donors stimulate proliferation of human endothelial cells in vitro. Cell Biol Int 28(6):483–486. doi:10.1016/j.cellbi.2004.03.004

    Article  PubMed  CAS  Google Scholar 

  25. Kosmidou I, Xagorari A, Roussos C, Papapetropoulos A (2001) Reactive oxygen species stimulate VEGF production from C(2) C(12) skeletal myotubes through a PI3 K/Akt pathway. Am J Physiol Lung Cell Mol Physiol 280(4):L585–L592

    PubMed  CAS  Google Scholar 

  26. Chen C, Li M, Chai H, Yang H, Fisher WE, Yao Q (2005) Roles of neuropilins in neuronal development, angiogenesis, and cancers. World J Surg 29(3):271–275. doi:10.1007/s00268-004-7818-1

    Article  PubMed  Google Scholar 

  27. Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ (2005) Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 131(9):624–630. doi:10.1007/s00432-005-0003-6

    Article  PubMed  CAS  Google Scholar 

  28. Claffey KP, Wilkison WO, Spiegelman BM (1992) Vascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem 267(23):16317–16322

    PubMed  CAS  Google Scholar 

  29. Guidi AJ, Schnitt SJ, Fischer L, Tognazzi K, Harris JR, Dvorak HF, Brown LF (1997) Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast. Cancer 80(10):1945–1953. doi:10.1002/(SICI)1097-0142(19971115)80:10<1945:AID-CNCR11>3.0.CO;2-Y

    Article  PubMed  CAS  Google Scholar 

  30. Madsen P, Rasmussen HH, Leffers H, Honore B, Dejgaard K, Olsen E, Kiil J, Walbum E, Andersen AH, Basse B et al (1991) Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. J Invest Dermatol 97(4):701–712

    Article  PubMed  CAS  Google Scholar 

  31. Schmidt AM, Hofmann M, Taguchi A, Yan SD, Stern DM (2000) RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. Semin Thromb Hemost 26(5):485–493. doi:10.1055/s-2000-13204

    Article  PubMed  CAS  Google Scholar 

  32. Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, Ito R, Yokozaki H, Yasui W (2002) Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 196(2):163–170. doi:10.1002/path.1031

    Article  PubMed  CAS  Google Scholar 

  33. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405(6784):354–360. doi:10.1038/35012626

    Article  PubMed  CAS  Google Scholar 

  34. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97(7):889–901

    Article  PubMed  CAS  Google Scholar 

  35. Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M (2008) S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 83(6):1484–1492. doi:10.1189/jlb.0607397

    Article  PubMed  CAS  Google Scholar 

  36. Farmer DG, Kennedy S (2009) RAGE, vascular tone and vascular disease. Pharmacol Ther 124(2):185–194. doi:10.1016/j.pharmthera.2009.06.013

    Article  PubMed  CAS  Google Scholar 

  37. Brauchle M, Funk JO, Kind P, Werner S (1996) Ultraviolet B and H2O2 are potent inducers of vascular endothelial growth factor expression in cultured keratinocytes. J Biol Chem 271(36):21793–21797

    Article  PubMed  CAS  Google Scholar 

  38. Chua CC, Hamdy RC, Chua BH (1998) Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Radic Biol Med 25(8):891–897

    Article  PubMed  CAS  Google Scholar 

  39. Burdon RH (1995) Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18(4):775–794

    Article  PubMed  CAS  Google Scholar 

  40. Benedyk M, Sopalla C, Nacken W, Bode G, Melkonyan H, Banfi B, Kerkhoff C (2007) HaCaT keratinocytes overexpressing the S100 proteins S100A8 and S100A9 show increased NADPH oxidase and NF-kappaB activities. J Invest Dermatol 127(8):2001–2011. doi:10.1038/sj.jid.5700820

    Article  PubMed  CAS  Google Scholar 

  41. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D (1994) Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 269(13):9889–9897

    PubMed  CAS  Google Scholar 

  42. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192(1):1–15. doi:10.1002/jcp.10119

    Article  PubMed  CAS  Google Scholar 

  43. Abid MR, Tsai JC, Spokes KC, Deshpande SS, Irani K, Aird WC (2001) Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. FASEB J 15(13):2548–2550. doi:10.1096/fj.01-0338fje

    PubMed  CAS  Google Scholar 

  44. Sauer H, Diedershagen H, Hescheler J, Wartenberg M (1997) Calcium-dependence of hydrogen peroxide-induced c-fos expression and growth stimulation of multicellular prostate tumor spheroids. FEBS Lett 419(2–3):201–205

    Article  PubMed  CAS  Google Scholar 

  45. Leclerc E, Fritz G, Weibel M, Heizmann CW, Galichet A (2007) S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem 282(43):31317–31331. doi:10.1074/jbc.M703951200

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Swedish Cancer Society, the Swedish Psoriasis Association, the Assar Gabrielsson Foundation, the Welander Foundation, and the Tore Nilsson Foundation.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden

    Emman Shubbar

  2. Department of Clinical and Experimental Medicine, Division of Cell Biology and Dermatology, Linköping University, 581 85, Linköping, Sweden

    Jenny Vegfors, Maria Carlström, Stina Petersson & Charlotta Enerbäck

Authors
  1. Emman Shubbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny Vegfors
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Carlström
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stina Petersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charlotta Enerbäck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charlotta Enerbäck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shubbar, E., Vegfors, J., Carlström, M. et al. Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation. Breast Cancer Res Treat 134, 71–80 (2012). https://doi.org/10.1007/s10549-011-1920-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1920-5

Keywords

Search

Navigation