[en] Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is not known. We investigated the effect of this protease on cell migration and angiogenesis in vitro and studied the expression of meprin-α mRNA, protein and proteolytic activity in primary tumors at progressive stages and in liver metastases of patients with colorectal cancer, as well as inhibitory activity towards meprin-α in sera of cancer patient as compared to healthy controls. We found that the hepatocyte growth factor (HGF)- induced migratory response of meprin-transfected epithelial cells was increased compared to wild-type cells in the presence of plasminogen, and that the angiogenic response in organ-cultured rat aortic explants was enhanced in the presence of exogenous human meprin-α. In patients, meprin-α mRNA was expressed in colonic adenomas, primary tumors UICC (International Union Against Cancer) stage I, II, III and IV, as well as in liver metastases. In contrast, the corresponding protein accumulated only in primary tumors and liver metastases, but not in adenomas. However, liver metastases lacked meprin-α activity despite increased expression of the corresponding protein, which correlated with inefficient zymogen activation. Sera from cancer patients exhibited reduced meprin-α inhibition compared to healthy controls. In conclusion, meprin-α activity is regulated differently in primary tumors and metastases, leading to high proteolytic activity in primary tumors and low activity in liver metastases. By virtue of its pro-migratory and pro-angiogenic activity, meprin-α may promote tumor progression in colorectal cancer.
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Egeblad M, Werb Z, (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161-174.
Wolf K, Wu YI, Liu Y, Geiger J, Tam E, et al. (2007) Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9: 893-904.
Dumermuth E, Sterchi EE, Jiang WP, Wolz RL, Bond JS, et al. (1991) The astacin family of metalloendopeptidases. J Biol Chem 266: 21381-21385.
Lottaz D, Maurer CA, Hahn D, Büchler MW, Sterchi EE, (1999) Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma. Cancer Res 59: 1127-1133.
Hahn D, Illisson R, Metspalu A, Sterchi EE, (2000) Human N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (human meprin): genomic structure of the alpha and beta subunits. Biochem J 346: 83-91.
Lottaz D, Hahn D, Müller S, Müller C, Sterchi EE, (1999) Secretion of human meprin from intestinal epithelial cells depends on differential expression of the alpha and beta subunits. Eur J Biochem 259: 496-504.
Becker C, Kruse MN, Slotty KA, Köhler D, Harris JR, et al. (2003) Differences in the activation mechanism between the alpha and beta subunits of human meprin. Biol Chem 384: 825-831.
Bertenshaw GP, Norcum MT, Bond JS, (2003) Structure of homo- and hetero-oligomeric meprin metalloproteases. Dimers, tetramers, and high molecular mass multimers. J Biol Chem 278: 2522-2532.
Bertenshaw GP, Turk BE, Hubbard SJ, Matters GL, Bylander JE, et al. (2001) Marked differences between metalloproteases meprin A and B in substrate and peptide bond specificity. J Biol Chem 276: 13248-13255.
Kruse MN, Becker C, Lottaz D, Köhler D, Yiallouros I, et al. (2004) Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J 378: 383-389.
Banerjee S, Bond JS, (2008) Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal inflammation. J Biol Chem 283: 31371-31377.
Becker-Pauly C, Barre O, Schilling O, Auf dem Keller U, Ohler A, et al. (2011) Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates. Mol Cell Proteomics.
Jefferson T, Causevic M, Auf dem Keller U, Schilling O, Isbert S, et al. (2011) The metalloprotease meprin {beta} generates non toxic N-terminal amyloid precursor protein fragments in vivo. J Biol Chem.
Schütte A, Hedrich J, Stöcker W, Becker-Pauly C, (2010) Let it flow: Morpholino knockdown in zebrafish embryos reveals a pro-angiogenic effect of the metalloprotease meprin alpha2. PLoS One 5: e8835.
Kaushal GP, Walker PD, Shah SV, (1994) An old enzyme with a new function: purification and characterization of a distinct matrix-degrading metalloproteinase in rat kidney cortex and its identification as meprin. J Cell Biol 126: 1319-1327.
Hirano M, Ma BY, Kawasaki N, Okimura K, Baba M, et al. (2005) Mannan-Binding Protein Blocks the Activation of Metalloproteases Meprin {alpha} and {beta}. J Immunol 175: 3177-3185.
Hedrich J, Lottaz D, Meyer K, Yiallouros I, Jahnen-Dechent W, et al. (2010) Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases. Biochemistry 49: 8599-8607.
Grünberg J, Dumermuth E, Eldering JA, Sterchi EE, (1993) Expression of the alpha subunit of PABA peptide hydrolase (EC 3.4.24.18) in MDCK cells. Synthesis and secretion of an enzymatically inactive homodimer. FEBS Lett 335: 376-379.
Rösmann S, Hahn D, Lottaz D, Kruse MN, Stöcker W, et al. (2002) Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system. J Biol Chem 277: 40650-40658.
Ohler A, Debela M, Wagner S, Magdolen V, Becker-Pauly C, (2010) Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol Chem 391: 455-460.
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF, (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4: 915-925.
Keller HU, Hunziker IP, Sordat B, Niggli V, Sroka J, (2000) Protein kinase C isoforms involved in regulation of cell shape and locomotion of human fibrosarcoma HT1080 cells. Int J Cancer 88: 195-203.
Devy L, Blacher S, Grignet-Debrus C, Bajou K, Masson V, et al. (2002) The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. Faseb J 16: 147-154.
Jiang W, Kumar JM, Matters GL, Bond JS, (2000) Structure of the mouse metalloprotease meprin beta gene (Mep1b): alternative splicing in cancer cells. Gene 248: 77-87.
Sterchi EE, Stöcker W, Bond JS, (2008) Meprins, membrane-bound and secreted astacin metalloproteinases. Mol Aspects Med 29: 309-328.
Jass JR, Whitehall VL, Young J, Leggett BA, (2002) Emerging concepts in colorectal neoplasia. Gastroenterology 123: 862-876.
Sier CF, Vloedgraven HJ, Ganesh S, Griffioen G, Quax PH, et al. (1994) Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis. Gastroenterology 107: 1449-1456.
Zucker S, Vacirca J, (2004) Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 23: 101-117.
Illemann M, Bird N, Majeed A, Sehested M, Laerum OD, et al. (2006) MMP-9 is differentially expressed in primary human colorectal adenocarcinomas and their metastases. Mol Cancer Res 4: 293-302.
Eldering JA, Grünberg J, Hahn D, Croes HJ, Fransen JA, et al. (1997) Polarised expression of human intestinal N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase (human meprin) alpha and beta subunits in Madin-Darby canine kidney cells. Eur J Biochem 247: 920-932.
Sier CF, Verspaget HW, Griffioen G, Verheijen JH, Quax PH, et al. (1991) Imbalance of plasminogen activators and their inhibitors in human colorectal neoplasia. Implications of urokinase in colorectal carcinogenesis. Gastroenterology 101: 1522-1528.
Delbaldo C, Cunningham M, Vassalli JD, Sappino AP, (1995) Plasmin-catalyzed proteolysis in colorectal neoplasia. Cancer Res 55: 4688-4695.
Suzuki S, Hayashi Y, Wang Y, Nakamura T, Morita Y, et al. (1998) Urokinase type plasminogen activator receptor expression in colorectal neoplasms. Gut 43: 798-805.
Mulcahy HE, Duffy MJ, Gibbons D, McCarthy P, Parfrey NA, et al. (1994) Urokinase-type plasminogen activator and outcome in Dukes' B colorectal cancer. Lancet 344: 583-584.
Köhler D, Kruse M, Stöcker W, Sterchi EE, (2000) Heterologously overexpressed, affinity-purified human meprin alpha is functionally active and cleaves components of the basement membrane in vitro. FEBS Lett 465: 2-7.
Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V, (2000) Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148: 615-624.
Khan KMF, Laurie GW, McCaffrey TA, Falcone DJ, (2002) Exposure of Cryptic Domains in the alpha 1-chain of Laminin-1 by Elastase Stimulates Macrophages Urokinase and Matrix Metalloproteinase-9 Expression. J Biol Chem 277: 13778-13786.
Bajou K, Noel A, Gerard RD, Masson V, Brunner N, et al. (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4: 923-928.
Huguenin M, Müller EJ, Trachsel-Rösmann S, Oneda B, Ambort D, et al. (2008) The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion. PLoS One 3: e2153.
Becker-Pauly C, Howel M, Walker T, Vlad A, Aufenvenne K, et al. (2007) The alpha and beta subunits of the metalloprotease meprin are expressed in separate layers of human epidermis, revealing different functions in keratinocyte proliferation and differentiation. J Invest Dermatol 127: 1115-1125.
Blacher S, Devy L, Burbridge MF, Roland G, Tucker G, et al. (2001) Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis 4: 133-142.
Maurer CA, Friess H, Kretschmann B, Wildi S, Müller C, et al. (1998) Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer. Int J Cancer 79: 76-81.
Sterchi EE, Green JR, Lentze MJ, (1983) Nonpancreatic hydrolysis of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (PABA peptide) in the rat small intestine. J Pediatr Gastroenterol Nutr 2: 539-547.
