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Myeloma

Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation

Leukemia volume 26, pages 2286–2296 (2012)Cite this article

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Abstract

Multiple myeloma (MM) is preceded by the asymptomatic pre-malignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be having an important biological role in MM. We first demonstrate that CD147 is overexpressed in MM plasma cells (PCs) vs normal and pre-malignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147bright and CD147dim populations and analyzed for proliferation potential, we discovered that CD147bright PCs displayed significantly higher levels of cell proliferation than did CD147dim PCs. Lastly, CD147-silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule has a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.

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References

  1. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113: 5412–5417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM . A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009; 113: 5418–5422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. International Myeloma Working G. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121: 749–757.

    Article  Google Scholar 

  4. Kyle RA, Rajkumar SV . Monoclonal gammopathy of undetermined significance. Br J Haematol 2006; 134: 573–589.

    Article  CAS  PubMed  Google Scholar 

  5. Kyle RA . ‘Benign’ monoclonal gammopathy—after 20 to 35 years of follow-up. Mayo Clin Proc 1993; 68: 26–36.

    Article  CAS  PubMed  Google Scholar 

  6. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111: 2516–2520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raja KR, Kovarova L, Hajek R . Review of phenotypic markers used in flow cytometric analysis of MGUS and MM, and applicability of flow cytometry in other plasma cell disorders. Br J Haematol 2010; 149: 334–351.

    Article  CAS  PubMed  Google Scholar 

  8. Iacono KT, Brown AL, Greene MI, Saouaf SJ . CD147 immunoglobulin superfamily receptor function and role in pathology. Exp Mol Pathol 2007; 83: 283–295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M . Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol 2010; 160: 305–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li Y, Xu J, Chen L, Zhong WD, Zhang Z, Mi L et al. HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection. Histopathology 2009; 54: 677–687.

    Article  CAS  PubMed  Google Scholar 

  11. van den Oord JJ, Paemen L, Opdenakker G, de Wolf-Peeters C . Expression of gelatinase B and the extracellular matrix metalloproteinase inducer EMMPRIN in benign and malignant pigment cell lesions of the skin. Am J Pathol 1997; 151: 665–670.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng HC, Takahashi H, Murai Y, Cui ZG, Nomoto K, Miwa S et al. Upregulated EMMPRIN/CD147 might contribute to growth and angiogenesis of gastric carcinoma: a good marker for local invasion and prognosis. Br J Cancer 2006; 95: 1371–1378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kanekura T, Chen X . CD147/basigin promotes progression of malignant melanoma and other cancers. J Dermatol Sci 2010; 57: 149–154.

    Article  CAS  PubMed  Google Scholar 

  14. Nawroth R, Stohr R, Hartmann A, Gschwend JE, Retz M . EMMPRIN (CD147). A new key protein during tumor progression in bladder cancer. Urologe A 2008; 47: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  15. Yan L, Zucker S, Toole BP . Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumour progression. Thromb Haemost 2005; 93: 199–204.

    Article  CAS  PubMed  Google Scholar 

  16. Tang Y, Nakada MT, Kesavan P, McCabe F, Millar H, Rafferty P et al. Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res 2005; 65: 3193–3199.

    Article  CAS  PubMed  Google Scholar 

  17. Sun J, Hemler ME . Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res 2001; 61: 2276–2281.

    CAS  PubMed  Google Scholar 

  18. Yang JM, O'Neill P, Jin W, Foty R, Medina DJ, Xu Z et al. Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to Anoikis through inhibition of Bim. J Biol Chem 2006; 281: 9719–9727.

    Article  CAS  PubMed  Google Scholar 

  19. Yurchenko V, O'Connor M, Dai WW, Guo H, Toole B, Sherry B et al. CD147 is a signaling receptor for cyclophilin B. Biochem Biophys Res Commun 2001; 288: 786–788.

    Article  CAS  PubMed  Google Scholar 

  20. Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T et al. Active site residues of cyclophilin A are crucial for its signaling activity via CD147. J Biol Chem 2002; 277: 22959–22965.

    Article  CAS  PubMed  Google Scholar 

  21. Pakula R, Melchior A, Denys A, Vanpouille C, Mazurier J, Allain F . Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis. Glycobiology 2007; 17: 492–503.

    Article  CAS  PubMed  Google Scholar 

  22. Allain F, Vanpouille C, Carpentier M, Slomianny MC, Durieux S, Spik G . Interaction with glycosaminoglycans is required for cyclophilin B to trigger integrin-mediated adhesion of peripheral blood T lymphocytes to extracellular matrix. Proc Natl Acad Sci USA 2002; 99: 2714–2719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bauer K, Kretzschmar AK, Cvijic H, Blumert C, Loffler D, Brocke-Heidrich K et al. Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells. Oncogene 2009; 28: 2784–2795.

    Article  CAS  PubMed  Google Scholar 

  24. Jelinek DF, Ahmann GJ, Greipp PR, Jalal SM, Westendorf JJ, Katzmann JA et al. Coexistence of aneuploid subclones within a myeloma cell line that exhibits clonal immunoglobulin gene rearrangement: clinical implications. Cancer Res 1993; 53: 5320–5327.

    CAS  PubMed  Google Scholar 

  25. Arendt BK, Ramirez-Alvarado M, Sikkink LA, Keats JJ, Ahmann GJ, Dispenzieri A et al. Biologic and genetic characterization of the novel amyloidogenic lambda light chain-secreting human cell lines, ALMC-1 and ALMC-2. Blood 2008; 112: 1931–1941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Westendorf JJ, Ahmann GJ, Greipp PR, Witzig TE, Lust JA, Jelinek DF . Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6. Leukemia 1996; 10: 866–876.

    CAS  PubMed  Google Scholar 

  27. Walters DK, Wu X, Tschumper RC, Arendt BK, Huddleston PM, Henderson KJ et al. Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX. Leukemia 2011; 25: 1344–1353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tschumper RC, Geyer SM, Campbell ME, Kay NE, Shanafelt TD, Zent CS et al. Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients. J Clin Invest 2008; 118: 306–315.

    Article  CAS  PubMed  Google Scholar 

  29. Walters DK, Jelinek DF . The effectiveness of double-stranded short inhibitory RNAs (siRNAs) may depend on the method of transfection. Antisense Nucleic Acid Drug Dev 2002; 12: 411–418.

    Article  CAS  PubMed  Google Scholar 

  30. Tang W, Chang SB, Hemler ME . Links between CD147 function, glycosylation, and caveolin-1. Mol Biol Cell 2004; 15: 4043–4050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tang W, Hemler ME . Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147/EMMPRIN cell surface clustering. J Biol Chem 2004; 279: 11112–11118.

    Article  CAS  PubMed  Google Scholar 

  32. Voigt H, Vetter-Kauczok CS, Schrama D, Hofmann UB, Becker JC, Houben R . CD147 impacts angiogenesis and metastasis formation. Cancer Invest 2009; 27: 329–333.

    Article  CAS  PubMed  Google Scholar 

  33. Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM et al. HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. Mol Cancer Res 2007; 5: 605–614.

    Article  CAS  PubMed  Google Scholar 

  34. Robillard N, Pellat-Deceunynck C, Bataille R . Phenotypic characterization of the human myeloma cell growth fraction. Blood 2005; 105: 4845–4848.

    Article  CAS  PubMed  Google Scholar 

  35. Caudroy S, Polette M, Tournier JM, Burlet H, Toole B, Zucker S et al. Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase-2 in bronchopulmonary and breast lesions. J Histochem Cytochem 1999; 47: 1575–1580.

    Article  CAS  PubMed  Google Scholar 

  36. Muraoka K, Nabeshima K, Murayama T, Biswas C, Koono M . Enhanced expression of a tumor-cell-derived collagenase-stimulatory factor in urothelial carcinoma: its usefulness as a tumor marker for bladder cancers. Int J Cancer 1993; 55: 19–26.

    Article  CAS  PubMed  Google Scholar 

  37. Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J, Kikuchi M . Emmprin (basigin/CD147): matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int 2006; 56: 359–367.

    Article  CAS  PubMed  Google Scholar 

  38. Steensma DP, Gertz MA, Greipp PR, Kyle RA, Lacy MQ, Lust JA et al. A high bone marrow plasma cell labeling index in stable plateau-phase multiple myeloma is a marker for early disease progression and death. Blood 2001; 97: 2522–2523.

    Article  CAS  PubMed  Google Scholar 

  39. Greipp PR, Lust JA, O'Fallon WM, Katzmann JA, Witzig TE, Kyle RA . Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood 1993; 81: 3382–3387.

    CAS  PubMed  Google Scholar 

  40. Kumar S, Rajkumar SV, Kimlinger T, Greipp PR, Witzig TE . CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations. Leukemia 2005; 19: 1466–1470.

    Article  CAS  PubMed  Google Scholar 

  41. Moreau P, Robillard N, Avet-Loiseau H, Pineau D, Morineau N, Milpied N et al. Patients with CD45 negative multiple myeloma receiving high-dose therapy have a shorter survival than those with CD45 positive multiple myeloma. Haematologica 2004; 89: 547–551.

    PubMed  Google Scholar 

  42. Menke DM, Horny HP, Griesser H, Atkinson EJ, Kaiserling E, Kyle RA . Immunophenotypic and genotypic characterisation of multiple myelomas with adverse prognosis characterised by immunohistological expression of the T cell related antigen CD45RO (UCHL-1). J Clin Pathol 1998; 51: 432–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mateo G, Montalban MA, Vidriales MB, Lahuerta JJ, Mateos MV, Gutierrez N et al. Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol 2008; 26: 2737–2744.

    Article  PubMed  Google Scholar 

  44. Yang Y, Lu N, Zhou J, Chen ZN, Zhu P . Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47: 1299–1310.

    Article  CAS  Google Scholar 

  45. Yurchenko V, Constant S, Bukrinsky M . Dealing with the family: CD147 interactions with cyclophilins. Immunology 2006; 117: 301–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li M, Zhai Q, Bharadwaj U, Wang H, Li F, Fisher WE et al. Cyclophilin A is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. Cancer 2006; 106: 2284–2294.

    Article  CAS  PubMed  Google Scholar 

  47. Baba M, Inoue M, Itoh K, Nishizawa Y . Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun 2008; 374: 111–116.

    Article  CAS  PubMed  Google Scholar 

  48. Chen X, Lin J, Kanekura T, Su J, Lin W, Xie H et al. A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness, and metastatic activity of malignant melanoma. Cancer Res 2006; 66: 11323–11330.

    Article  CAS  PubMed  Google Scholar 

  49. Chen X, Su J, Chang J, Kanekura T, Li J, Kuang YH et al. Inhibition of CD147 gene expression via RNA interference reduces tumor cell proliferation, activation, adhesion, and migration activity in the human Jurkat T-lymphoma cell line. Cancer Invest 2008; 26: 689–697.

    Article  CAS  PubMed  Google Scholar 

  50. Wang B, Xu YF, He BS, Pan YQ, Zhang LR, Zhu C et al. RNAi-mediated silencing of CD147 inhibits tumor cell proliferation, invasion and increases chemosensitivity to cisplatin in SGC7901 cells in vitro. J Exp Clin Cancer Res 2010; 29: 61.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Rajkumar SV, Mesa RA, Fonseca R, Schroeder G, Plevak MF, Dispenzieri A et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 2002; 8: 2210–2216.

    PubMed  Google Scholar 

  52. Ribatti D, Vacca A, Nico B, Quondamatteo F, Ria R, Minischetti M et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 1999; 79: 451–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson RD . Matrix metalloproteinases in multiple myeloma. Leuk Lymphoma 2000; 37: 273–281.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by the Multiple Myeloma Research Foundation, a grant from the National Institutes of Health (CA164232; awarded to DFJ), and the JABBS and Predolin Foundations.

Author contributions

BKA designed and performed research, analyzed data and wrote the manuscript. DKW, XW, RCT and KJH performed research and analyzed data. PMH and AD designed research and enrolled patients. DFJ designed research and wrote and approved the manuscript. All the authors reviewed and gave final approval of the manuscript.

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Authors and Affiliations

  1. Department of Immunology, Mayo Clinic, College of Medicine, Rochester, MN, USA

    B K Arendt, D K Walters, X Wu, R C Tschumper & D F Jelinek

  2. Department of Orthopedic Surgery, Mayo Clinic, College of Medicine, Rochester, MN, USA

    P M Huddleston

  3. Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA

    K J Henderson & A Dispenzieri

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  1. B K Arendt
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Correspondence to D F Jelinek.

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Arendt, B., Walters, D., Wu, X. et al. Increased expression of extracellular matrix metalloproteinase inducer (CD147) in multiple myeloma: role in regulation of myeloma cell proliferation. Leukemia 26, 2286–2296 (2012). https://doi.org/10.1038/leu.2012.91

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