the metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.

[en] Objectives: The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human non-small cell lung cancers. The aim of this study was to investigate the roles played by ADAM-12 in critical steps of bronchial cell transformation during carcinogenesis. Materials and methods: To assess the role of ADAM-12 in tumorigenicity, BEAS-2B cells were transfected with a plasmid encoding human full-length ADAM-12 cDNA, and then the effects of ADAM-12 overexpression on cell behaviour were explored. Treatment of clones with heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) neutralizing antibodies as well as an EGFR inhibitor allowed the dissection of mechanisms regulating cell proliferation and apoptosis. Results: Overexpression of ADAM-12 in BEAS-2B cells promoted cell proliferation. ADAM-12 overexpressing clones produced higher quantities of HB-EGF in their culture medium which may rely on membrane-bound HB-EGF shedding by ADAM-12. Targeting HB-EGF activity with a neutralizing antibody abrogated enhanced cell proliferation in the ADAM-12 overexpressing clones. In sharp contrast, targeting of amphiregulin, EGF or transforming growth factor-α failed to influence cell proliferation; moreover, ADAM-12 transfectants were resistant to etoposide-induced apoptosis and the use of a neutralizing antibody against HB-EGF activity restored rates of apoptosis to be similar to controls. Conclusions: ADAM-12 contributes to enhancing HB-EGF shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line.

Research Center/Unit :

Giga-Cancer - ULiège

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology

Author, co-author :

Rocks, Natacha ^✱; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Estrella, C. ^✱

Paulissen, Geneviève ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Quesada Calvo, Florence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques

Gilles, Christine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Guéders, Maud ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Crahay, Céline

Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement

Gosset, Ph

Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Cataldo, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement - Département des sciences biomédicales et précliniques

^✱ These authors have contributed equally to this work.

Language :

English

Title :

the metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.

Publication date :

2008

Journal title :

Cell Proliferation

ISSN :

0960-7722

eISSN :

1365-2184

Publisher :

Blackwell Publishing, Oxford, United Kingdom

Volume :

Issue :

Pages :

988-1001

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 10 March 2009

Statistics

Number of views

203 (20 by ULiège)

Number of downloads

208 (8 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, Ohmoto H, Node K, Yoshino K, Ishiguro H, Asanuma H, Sanada S, Matsumura Y, Takeda H, Beppu S, Tada M, Hori M, Higashiyama S (2002) Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat. Med. 8, 35 40.
Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729 733.
Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Rocken C (2005) The disintegrin metalloproteinases ADAM9, ADAM12, and ADAM15 are up-regulated in gastric cancer. Int. J. Oncol. 26, 17 24.
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161 174.
Freedman VH, Shin SI (1974) Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium. Cell 3, 355 359.
Frohlich C, Albrechtsen R, Dyrskjot L, Rudkjaer L, Orntoft TF, Wewer UM (2006) Molecular profiling of ADAM12 in human bladder cancer. Clin. Cancer Res. 12, 7359 7368.
Gack S, Marme A, Marme F, Wrobel G, Vonderstrass B, Bastert G, Lichter P, Angel P, Schorpp-Kistner M (2005) Preeclampsia: increased expression of soluble ADAM 12. J. Mol. Med. 83, 887 896.
Gee JM, Knowlden JM (2003) ADAM metalloproteases and EGFR signalling. Breast Cancer Res. 5, 223 224.
Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM (1998) A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo. J. Biol. Chem. 273, 157 166.
Higashiyama S, Nanba D (2005) ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk. Biochim. Biophys. Acta 1751, 110 117.
Huovila AP, Turner AJ, Pelto-Huikko M, Karkkainen I, Ortiz RM (2005) Shedding light on ADAM metalloproteinases. Trends Biochem. Sci. 30, 413 422.
Iba K, Albrechtsen R, Gilpin B, Frohlich C, Loechel F, Zolkiewska A, Ishiguro K, Kojima T, Liu W, Langford JK, Sanderson RD, Brakebusch C, Fassler R, Wewer UM (2000) The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading. J. Cell Biol. 149, 1143 1156.
Iba K, Albrechtsen R, Gilpin BJ, Loechel F, Wewer UM (1999) Cysteine-rich domain of human ADAM 12 (meltrin alpha) supports tumor cell adhesion. Am. J. Pathol. 154, 1489 1501.
Itoh Y, Joh T, Tanida S, Sasaki M, Kataoka H, Itoh K, Oshima T, Ogasawara N, Togawa S, Wada T, Kubota H, Mori Y, Ohara H, Nomura T, Higashiyama S, Itoh M (2005) IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells. Cytokine 29, 275 282.
Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat. Rev. Cancer 6, 392 401.
Kawaguchi N, Xu X, Tajima R, Kronqvist P, Sundberg C, Loechel F, Albrechtsen R, Wewer UM (2002) ADAM 12 protease induces adipogenesis in transgenic mice. Am. J. Pathol. 160, 1895 1903.
Kodama T, Ikeda E, Okada A, Ohtsuka T, Shimoda M, Shiomi T, Yoshida K, Nakada M, Ohuchi E, Okada Y (2004) ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am. J. Pathol. 165, 1743 1753.
Kveiborg M, Frohlich C, Albrechtsen R, Tischler V, Dietrich N, Holck P, Kronqvist P, Rank F, Mercurio AM, Wewer UM (2005) A role for ADAM12 in breast tumor progression and stromal cell apoptosis. Cancer Res. 65, 4754 4761.
Labarca C, Paigen K (1980) A simple, rapid, and sensitive DNA assay procedure. Anal. Biochem. 102, 344 352.
Laboisse CL, Augeron C, Potet F (1981) Growth and differentiation of human gastrointestinal adenocarcinoma stem cells in soft agarose. Cancer Res. 41, 310 315.
Laigaard J, Christiansen M, Frohlich C, Pedersen BN, Ottesen B, Wewer UM (2005a) The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18. Prenat. Diagn. 25, 45 46.
Laigaard J, Sorensen T, Placing S, Holck P, Frohlich C, Wojdemann KR, Sundberg K, Shalmi AC, Tabor A, Norgaard-Pedersen B, Ottesen B, Christiansen M, Wewer UM (2005b) Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia. Obstet. Gynecol. 106, 144 149.
Laigaard J, Spencer K, Christiansen M, Cowans NJ, Larsen SO, Pedersen BN, Wewer UM (2006) ADAM12 as a first-trimester maternal serum marker in screening for Down syndrome. Prenat. Diagn. 26, 973 979.
Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, Clement B, Theret N (2003) ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling. Hepatology 37, 1056 1066.
Lemjabbar H, Li D, Gallup M, Sidhu S, Drori E, Basbaum C (2003) Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J. Biol. Chem. 278, 26202 26207.
Lendeckel U, Kohl J, Arndt M, Carl-McGrath S, Donat H, Rocken C (2005) Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J. Cancer Res. Clin. Oncol. 131, 41 48.
Liu YJ, Xu Y, Yu Q (2006) Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 25, 2452 2467.
Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM (2000) ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem. Biophys. Res. Commun. 278, 511 515.
Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM (1998) Human ADAM 12 (meltrin alpha) is an active metalloprotease. J. Biol. Chem. 273, 16993 16997.
Lu X, Lu D, Scully MF, Kakkar VV (2005) Snake venom metalloproteinase containing a disintegrin-like domain, its structure-activity relationships at interacting with integrins. Curr. Med. Chem. Cardiovasc. Hematol. Agents 3, 249 260.
Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc. Natl. Acad. Sci. USA 102, 9182 9187.
Masaki M, Kurisaki T, Shirakawa K, Sehara-Fujisawa A (2005) Role of meltrin alpha (ADAM12) in obesity induced by high-fat diet. Endocrinology 146, 1752 1763.
Noel AC, Calle A, Emonard HP, Nusgens BV, Simar L, Foidart J, Lapiere CM, Foidart JM (1991) Invasion of reconstituted basement membrane matrix is not correlated to the malignant metastatic cell phenotype. Cancer Res. 51, 405 414.
Noel A, Jost M, Maquoi E (2008) Matrix metalloproteinases at cancer tumor-host interface. Semin. Cell Dev. Biol. 19, 52 60.
Noel A, Pauw-Gillet MC, Purnell G, Nusgens B, Lapiere CM, Foidart JM (1993) Enhancement of tumorigenicity of human breast adenocarcinoma cells in nude mice by Matrigel and fibroblasts. Br. J. Cancer 68, 909 915.
Ohtsu H, Dempsey PJ, Eguchi S (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am. J. Physiol. Cell Physiol. 291, C1 C10.
Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA (1998) An essential role for ectodomain shedding in mammalian development. Science 282, 1281 1284.
Rigas JR, Kelly K (2007) Current treatment paradigms for locally advanced non-small cell lung cancer. J. Thorac. Oncol. 2 (Suppl. 2 S77 S85.
Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D (2008) Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie 90, 369 379.
Rocks N, Paulissen G, Quesada CF, Polette M, Gueders M, Munaut C, Foidart JM, Noel A, Birembaut P, Cataldo D (2006) Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC). Br. J. Cancer 94, 724 730.
Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA (2004) ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J. Biol. Chem. 279, 51323 51330.
Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J. Cell Biol. 164, 769 779.
Schafer B, Marg B, Gschwind A, Ullrich A (2004) Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. J. Biol. Chem. 279, 47929 47938.
Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ (2000) ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J. Biol. Chem. 275, 18574 18580.
Tanaka Y, Miyamoto S, Suzuki SO, Oki E, Yagi H, Sonoda K, Yamazaki A, Mizushima H, Maehara Y, Mekada E, Nakano H (2005) Clinical significance of heparin-binding epidermal growth factor-like growth factor and a disintegrin and metalloprotease 17 expression in human ovarian cancer. Clin. Cancer Res. 11, 4783 4792.
Wewer UM, Morgelin M, Holck P, Jacobsen J, Lydolph MC, Johnsen AH, Kveiborg M, Albrechtsen R (2006) ADAM12 is a four-leafed clover: the excised prodomain remains bound to the mature enzyme. J. Biol. Chem. 281, 9418 9422.
Yagami-Hiromasa T, Sato T, Kurisaki T, Kamijo K, Nabeshima Y, Fujisawa-Sehara A (1995) A metalloprotease-disintegrin participating in myoblast fusion. Nature 377, 652 656.
Yan Y, Shirakabe K, Werb Z (2002) The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J. Cell Biol. 158, 221 226.