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C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression

Oncogene volume 37, pages 28–38 (2018)Cite this article

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Abstract

C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . Cancer statistics. CA Cancer J Clin 2007; 57: 43–66.

    Article  PubMed Central  Google Scholar 

  2. André F, Zielinski CC . Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents. Ann Oncol 2012; 23: 46–51.

    Article  Google Scholar 

  3. Chambers AF, Groom AC, MacDonald IC . Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2: 563–572.

    Article  CAS  Google Scholar 

  4. Balkwill F, Mantovani A . Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539–545.

    Article  CAS  Google Scholar 

  5. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A . Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30: 1073–1081.

    Article  CAS  Google Scholar 

  6. Hojilla CV, Wood GA, Khokha R . Inflammation and breast cancer: metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer. Breast Cancer Res 2008; 10: 205.

    Article  PubMed Central  Google Scholar 

  7. Ames BN, Gold LS, Willett WC . The causes and prevention of cancer. Proc Natl Acad Sci USA 1995; 92: 5258–5265.

    Article  CAS  Google Scholar 

  8. Platz EA, De Marzo AM . Epidemiology of inflammation and prostate cancer. J Urol 2004; 171: S36–S40.

    Article  Google Scholar 

  9. Gurleyik E, Gurleyik G, Unalmiser S . Accuracy of serum C-reactive protein measurements in diagnosis of acute appendicitis compared with surgeon’s clinical impression. Dis Colon Rectum 1995; 38: 1270–1274.

    Article  CAS  Google Scholar 

  10. Rodriguez-Sanjuan JC, Martin-Parra JI, Seco I, Garcia-Castrillo L, Naranjo A . C-reactive protein and leukocyte count in the diagnosis of acute appendicitis in children. Dis Colon Rectum 1999; 42: 1325–1329.

    Article  CAS  Google Scholar 

  11. Allin KH, Nordestgaard BG, Flyger H, Bojesen SE . Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study. Breast Cancer Res 2011; 13: R55.

    Article  CAS  PubMed Central  Google Scholar 

  12. Ravishankaran P, Karunanithi R . Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients. World J Surg Oncol 2011; 9: 18.

    Article  PubMed Central  Google Scholar 

  13. Kim ES, Cha Y, Ham M, Jung J, Kim SG, Hwang S et al. Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression. Oncogene 2014; 33: 3583–3593.

    Article  CAS  Google Scholar 

  14. Howe A, Aplin AE, Alahari SK, Juliano RL . Integrin signaling and cell growth control. Curr Opin Cell Biol 1998; 10: 220–231.

    Article  CAS  Google Scholar 

  15. Bendas G, Borsig L . Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012; 2012: 676731–676740.

    Article  PubMed Central  Google Scholar 

  16. Mego M, Mani SA, Cristofanilli M . Molecular mechanisms of metastasis in breast cancer – clinical applications. Nat Rev Clin Oncol 2010; 7: 693–701.

    Article  CAS  Google Scholar 

  17. Bartolomé RA, Barderas R, Torres S, Fernandez-Aceñero MJ, Mendes M, García-Foncillas J et al. Cadherin-17 interacts with α2β1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis. Oncogene 2014; 33: 1658–1669.

    Article  Google Scholar 

  18. Guo YS, Zhao R, Ma J, Cui W, Sun Z, Gao B et al. βig-h3 promotes human osteosarcoma cells metastasis by interacting with integrin α2β1 and activating PI3K signaling pathway. PLoS One 2014; 9: e90220.

    Article  PubMed Central  Google Scholar 

  19. Maric G, Annis MG, Dong Z, Rose AA, Ng S, Perkins D et al. GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis. Oncogene 2015; 34: 5494–5504.

    Article  CAS  Google Scholar 

  20. Hynes RO . Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673–687.

    Article  CAS  Google Scholar 

  21. Koukoulis GK, Howeedy AA, Korhonen M, Virtanen I, Gould VE . Distribution of tenascin, cellular fibronectins and integrins in the normal, hyperplastic and neoplastic breast (review). J Submicrosc Cytol Pathol 1993; 25: 285–295.

    CAS  PubMed  Google Scholar 

  22. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R . Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 2003; 63: 8312–8317.

    CAS  PubMed  Google Scholar 

  23. Zou CY, Wen FQ, Chen YX, Liu ZP, Zhang ZX . Effect of integrin alpha2beta1 on invasion and migration of neuroblastoma cells. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10: 386–390.

    CAS  PubMed  Google Scholar 

  24. Tsaur I, Makarević J, Juengel E, Gasser M, Waaga-Gasser AM, Kurosch M et al. Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and β1-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer 2012; 107: 847–855.

    Article  CAS  PubMed Central  Google Scholar 

  25. Ibaragi S, Shimo T, Hassan NM, Isowa S, Kurio N, Mandai H et al. Induction of MMP-13 expression in bone-metastasizing cancer cells by type I collagen through integrin α1β1 and α2β1-p38 MAPK signaling. Anticancer Res 2011; 31: 1307–1313.

    CAS  PubMed  Google Scholar 

  26. Fujita M, Takada YK, Izumiya Y, Takada Y . The binding of monomeric C-reactive protein (mCRP) to Integrins αvβ3 and α4β1 is related to its pro-inflammatory action. PLoS One 2014; 9: e93738.

    Article  PubMed Central  Google Scholar 

  27. Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES et al. Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL. J Biol Chem 1995; 270: 5039–5047.

    Article  CAS  Google Scholar 

  28. Schaller MD, Parsons JT . pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 1995; 15: 2635–2645.

    Article  CAS  PubMed Central  Google Scholar 

  29. Weng Z, Taylor JA, Turner CE, Brugge JS, Seidel-Dugan C . Detection of Src homology 3-binding proteins, including paxillin, in normal and v-Src-transformed BALB/c 3T3 cells. J Biol Chem 1993; 268: 14956–14963.

    CAS  PubMed  Google Scholar 

  30. Turner CE . Paxillin and focal adhesion signalling (review). Nat Cell Biol 2000; 2: E231–E236.

    Article  CAS  Google Scholar 

  31. Soule HD, Maloney TM, Wolman SR, Peterson WD Jr, Brenz R, McGrath CM et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 1990; 50: 6075–6086.

    CAS  PubMed  Google Scholar 

  32. Qu Y, Han B, Yu Y, Yao W, Bose S, Karlan BY et al. Evaluation of MCF10A as a reliable model for normal human mammary epithelial cells. PLoS One 2015; 10: e0131285.

    Article  PubMed Central  Google Scholar 

  33. Young B, Gleeson M, Cripps AW . C-reactive protein: a critical review. Pathology 1991; 23: 118–124.

    Article  CAS  Google Scholar 

  34. Ye J, Xu RH, Taylor-Papadimitriou J, Pitha PM . Sp1 binding plays a critical role in Erb-B2- and v-ras-mediated downregulation of alpha2-integrin expression in human mammary epithelial cells. Mol Cell Biol 1996; 16: 6178–6189.

    Article  CAS  PubMed Central  Google Scholar 

  35. Zutter MM, Santoro SA, Painter AS, Tsung YL, Gafford A . The human alpha 2 integrin gene promoter. Identification of positive and negative regulatory elements important for cell-type and developmentally restricted gene expression. J Biol Chem 1994; 269: 463–469.

    CAS  PubMed  Google Scholar 

  36. Sawhney RS, Sharma B, Humphrey LE, Brattain MG . Integrin alpha2 and extracellular signal-regulated kinase are functionally linked in highly malignant autocrine transforming growth factor-alpha-driven colon cancer cells. J Biol Chem 2003; 278: 19861–19869.

    Article  CAS  Google Scholar 

  37. Hanks SK, Ryzhova L, Shin NY, Brábek J . Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility (review). Front Biosci 2003; 8: d982–d996.

    Article  CAS  Google Scholar 

  38. Chi M, Tridandapani S, Zhong W, Coggeshall KM, Mortensen RF . C-reactive protein induces signaling through Fc gamma RIIa on HL-60 granulocytes. J Immunol 2002; 168: 1413–1418.

    Article  CAS  Google Scholar 

  39. Ortiz-Stern A, Rosales C . Cross-talk between Fc receptors and integrins. Immunol Lett 2003; 90: 137–143.

    Article  CAS  Google Scholar 

  40. Depraetere S, Willems J, Joniau M . Stimulation of CRP secretion in HepG2 cells: cooperative effect of dexamethasone and interleukin 6. Agents Actions 1991; 34: 369–375.

    Article  CAS  Google Scholar 

  41. Venugopal SK, Devaraj S, Jialal I . Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: potential for paracrine/autocrine effects. Am J Pathol 2005; 166: 1265–1271.

    Article  CAS  PubMed Central  Google Scholar 

  42. Mira E, Lacalle RA, Gómez-Moutón C, Leonardo E, Mañes S . Quantitative determination of tumor cell intravasation in a real-time polymerase chain reaction-based assay. Clin Exp Metastasis 2002; 19: 313–318.

    Article  CAS  Google Scholar 

  43. Ridker PM . From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res 2016; 118: 145–156.

    Article  CAS  PubMed Central  Google Scholar 

  44. Indik ZK, Hunter S, Huang MM, Pan XQ, Chien P, Kelly C et al. The high affinity Fc gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma subunit of Fc gamma RIIIA imparts phagocytic function to Fc gamma RI. Exp Hematol 1994; 22: 599–606.

    CAS  PubMed  Google Scholar 

  45. Knupfer H, Preiss R . Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 2007; 102: 129–135.

    Article  Google Scholar 

  46. Pierce BL, Ballard-Barbash R, Bernstein L, Baumgartner RN, Neuhouser ML, Wener MH et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 2009; 27: 3437–4344.

    Article  CAS  PubMed Central  Google Scholar 

  47. Maemura M, Akiyama SK, Woods VL Jr, Dickson RB . Expression and ligand binding of alpha 2 beta 1 integrin on breast carcinoma cells. Clin Exp Metastasis 1995; 13: 223–235.

    Article  CAS  Google Scholar 

  48. Yoshimura K, Meckel KF, Laird LS, Chia CY, Park JJ, Olino KL et al. Integrin alpha2 mediates selective metastasis to the liver. Cancer Res 2009; 69: 7320–7328.

    Article  CAS  PubMed Central  Google Scholar 

  49. Ramirez NE, Zhang Z, Madamanchi A, Boyd KL, O'Rear LD, Nashabi A et al. The α2β1 integrin is a metastasis suppressor in mouse models and human cancer. J Clin Invest 2011; 121: 226–237.

    Article  CAS  Google Scholar 

  50. Woollard KJ, Fisch C, Newby R, Griffiths HR . C-reactive protein mediates CD11b expression in monocytes through the non-receptor tyrosine kinase, Syk, and calcium mobilization but not through cytosolic peroxides. Inflamm Res 2005; 54: 485–492.

    Article  CAS  Google Scholar 

  51. Schaller MD . FAK and paxillin: regulators of N-cadherin adhesion and inhibitors of cell migration? (review).. J Cell Biol 2004; 166: 157–159.

    Article  CAS  PubMed Central  Google Scholar 

  52. Cance WG, Golubovskaya VM . Focal adhesion kinase versus p53: apoptosis or survival? Sci Signal 2008; 1: pe22.

    Article  PubMed Central  Google Scholar 

  53. Golubovskaya VM, Figel S, Ho BT, Johnson CP, Yemma M, Huang G et al. A small molecule focal adhesion kinase (FAK) inhibitor, targeting Y397 site: 1-(2-hydroxyethyl)-3, 5, 7-triaza-1-azoniatricyclo [3.3.1.1(3,7)]decane; bromide effectively inhibits FAK autophosphorylation activity and decreases cancer cell viability, clonogenicity and tumor growth in vivo. Carcinogenesis 2012; 33: 1004–1013.

    Article  CAS  PubMed Central  Google Scholar 

  54. Monteiro RC, Van De Winkel JG . IgA Fc receptors (review). Annu Rev Immunol 2003; 21: 177–204.

    Article  CAS  Google Scholar 

  55. Schmidt RE, Gessner JE . Fc receptors and their interaction with complement in autoimmunity (review). Immunol Lett 2005; 100: 56–67.

    Article  CAS  Google Scholar 

  56. Yang J, Wezeman M, Zhang X, Lin P, Wang M, Qian J et al. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell 2007; 12: 252–265.

    Article  Google Scholar 

  57. Haimovich B, Regan C, DiFazio L, Ginalis E, Ji P, Purohit U et al. The FcgammaRII receptor triggers pp125FAK phosphorylation in platelets. J Biol Chem 1996; 271: 16332–16337.

    Article  CAS  Google Scholar 

  58. Galon J, Gauchat JF, Mazières N, Spagnoli R, Storkus W, Lötze M et al. Soluble Fcgamma receptor type III (FcgammaRIII, CD16) triggers cell activation through interaction with complement receptors. J Immunol 1996; 157: 1184–1192.

    CAS  PubMed  Google Scholar 

  59. Metzger-Filho O, Tutt A, de Azambuja E, Saini KS, Viale G, Loi S et al. Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol 2012; 30: 1879–1887.

    Article  CAS  Google Scholar 

  60. Moon A, Kim MS, Kim TG, Kim SH, Kim HE, Chen YQ et al. H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: a role for MMP-2 in the H-ras induced invasive phenotype. Int J Cancer 2000; 85: 176–181.

    Article  CAS  Google Scholar 

  61. Lee HM, Moon A . Amygdalin regulates apoptosis and adhesion in Hs578T triple-negative breast cancer cells. Biomol Ther (Seoul) 2016; 24: 62–66.

    Article  CAS  Google Scholar 

  62. Kim MS, Lee EJ, Kim HRC, Moon A . p38 kinase is a key signaling molecule for H-ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 2003; 63: 5454–5461.

    CAS  PubMed  Google Scholar 

  63. Hwang HS, Park IY, Kim DW, Choi SY, Jung YO, Kim HA . PEP-1-FK506BP12 inhibits matrix metalloproteinase expression in human articular chondrocytes and in a mouse carrageenan-induced arthritis model. BMB Rep 2015; 48: 407–412.

    Article  CAS  PubMed Central  Google Scholar 

  64. Song H, Ki SH, Kim SG, Moon A . Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells. Cancer Res 2006; 66: 10487–10496.

    Article  CAS  Google Scholar 

  65. Kim ES, Kim JS, Kim SG, Hwang S, Lee CH, Moon A . Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Gαq coupling. J Cell Sci 2011; 124: 2220–2230.

    Article  CAS  Google Scholar 

  66. Kim KM, Lim HK, Shim SH, Jung J . Improved chemotherapeutic efficacy of injectable chrysin encapsulated by copolymer nanoparticles. Int J Nanomedicine 2017; 12: 1917–1925.

    Article  CAS  PubMed Central  Google Scholar 

  67. Koh M, Woo Y, Valiathan RR, Jung HY, Park SY, Kim YN et al. Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition. Int J Cancer 2015; 136: E508–E520.

    Article  CAS  Google Scholar 

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Acknowledgements

The present study was supported by Priority Research Centers Program (no. 2016R1A6A1A03007648), the Bio & Medical Technology Development Program (no. 2015M3A9B6074045) and Basic Science Program (no. 2014R1A6A3A01059908) of the NRF funded by the Korean government.

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Authors and Affiliations

  1. Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul, Korea

    E-S Kim, S Y Kim, M Koh, H-M Lee, K Kim, J Jung & A Moon

  2. Department of Radiology, Seoul National University Hospital, Seoul, Korea

    H S Kim & W K Moon

  3. College of Medicine, Hanyang University, Seoul, Korea

    S Hwang

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  1. E-S Kim
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Kim, ES., Kim, S., Koh, M. et al. C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression. Oncogene 37, 28–38 (2018). https://doi.org/10.1038/onc.2017.298

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