Abstract
We previously identified constitutive Smad signaling in human melanoma cells despite resistance to transforming growth factor-β (TGF-β) control of cell proliferation. This led us to investigate the effect of inhibitory Smad7 overexpression on melanoma cell behavior. Using the highly metastatic cell line, 1205-Lu, we thus generated melanoma cell clones constitutively expressing Smad7, and their mock-transfected counterparts. Stable expression of Smad7 resulted in an inhibition of constitutive Smad2/3 phosphorylation, and in a reduced TGF-β response of Smad3/Smad4-driven gene transactivation, as measured using transfected Smad3/4-specific reporter gene constructs. Smad7 overexpression, however, did not alter their proliferative capacity and resistance to TGF-β-driven growth inhibition. On the other hand, expression of Smad7 efficiently reduced the capacity of human melanoma cells to invade Matrigel in Boyden migration chambers, while not affecting their motility and adhesion to collagen and laminin. Gelatin zymography identified reduced MMP-2 and MMP-9 secretion by Smad7-expressing melanoma cells as compared with their control counterparts. Smad7-expressing melanoma cells exhibited a dramatically reduced capacity to form colonies under anchorage-independent culture conditions, and, when injected subcutaneously into nude mice, were largely delayed in their ability to form tumors. These results suggest that TGF-β production by melanoma cells not only affects the tumor environment but also directly contributes to tumor cell aggressiveness through autocrine activation of Smad signaling.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- ECM:
-
extracellular matrix
- MMP:
-
matrix metalloproteinase
- TGF-β:
-
transforming growth factor-β
References
Akhurst RJ and Derynck R . (2001). Trends Cell. Biol., 11, S44–S51.
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z and Hanahan D . (2000). Nat. Cell. Biol., 2, 737–744.
Berking C, Takemoto R, Schaider H, Showe L, Satyamoorthy K, Robbins P and Herlyn M . (2001). Cancer Res., 61, 8306–8316.
Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH and Leof EB . (2004). J. Clin. Invest., 114, 1308–1316.
Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier JM . (1998). EMBO J., 17, 3091–3100.
Gold LI . (1999). Crit. Rev. Oncog., 10, 303–360.
Hofmann UB, Westphal JR, Van Muijen GN and Ruiter DJ . (2000). J. Invest. Dermatol., 115, 337–344.
Javelaud D, Laboureau J, Gabison E, Verrecchia F and Mauviel A . (2003). J. Biol. Chem., 278, 24624–24628.
Javelaud D and Mauviel A . (2004). Int. J. Biochem. Cell. Biol., 36, 1161–1165.
Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K and Miyazawa K . (2004). Oncogene, 23, 6914–6923.
Ludwig T, Ossig R, Graessel S, Wilhelmi M, Oberleithner H and Schneider SW . (2002). Am. J. Physiol. Renal. Physiol., 283, F319–27.
MacDougall JR, Kobayashi H and Kerbel RS . (1993). Mol. Cell. Diff., 1, 21–40.
Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH and ten Dijke P . (1997). Nature, 389, 631–635.
Nakao A, Okumura K and Ogawa H . (2002). Trends Mol. Med., 8, 361–363.
Reed JA, Bales E, Xu W, Okan NA, Bandyopadhyay D and Medrano EE . (2001). Cancer Res., 61, 8074–8078.
Rodeck U, Bossler A, Graeven U, Fox FE, Nowell PC, Knabbe C and Kari C . (1994). Cancer Res., 54, 575–581.
Rodeck U, Nishiyama T and Mauviel A . (1999). Cancer Res., 59, 547–550.
Shi W, Sun C, He B, Xiong W, Shi X, Yao D and Cao X . (2004). J. Cell. Biol., 164, 291–300.
Shi Y and Massague J . (2003). Cell., 113, 685–700.
Siegel PM and Massague J . (2003). Nat. Rev. Cancer, 3, 807–821.
Stamenkovic I . (2000). Semin. Cancer Biol., 10, 415–433.
Wakefield LM and Roberts AB . (2002). Curr. Opin. Genet. Dev., 12, 22–29.
Xavier S, Piek E, Fujii M, Javelaud D, Mauviel A, Flanders KC, Samuni AM, Felici A, Reiss M, Yarkoni S, Sowers A, Mitchell JB, Roberts AB and Russo A . (2004). J. Biol. Chem., 279, 15167–15176.
Acknowledgements
We are thankful to Drs Meenhard Herlyn (Wistar Institute, Philadelphia, PA, USA), Sylviane Dennler and Jean-Michel Gauthier (Glaxo-Wellcome, Les Ulis, France), Edward Leof (Mayo Clinic, Rochester, MN, USA), and Peter ten Dijke (Leyden, The Netherlands) for providing us with reagents essential for these studies. The authors also wish to thank Christophe Alberti (Animal facility, Institut Curie, Orsay, France) for skillful technical help. This work was supported by grants from INSERM, Association pour la Recherche contre le Cancer (ARC), and Ligue Nationale Contre le Cancer (LNCC, section de Paris), France. DJ is the recipient of an ARC postdoctoral fellowship.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Javelaud, D., Delmas, V., Möller, M. et al. Stable overexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo. Oncogene 24, 7624–7629 (2005). https://doi.org/10.1038/sj.onc.1208900
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208900
Keywords
This article is cited by
-
miR-367 promotes epithelial-to-mesenchymal transition and invasion of pancreatic ductal adenocarcinoma cells by targeting the Smad7-TGF-β signalling pathway
British Journal of Cancer (2015)
-
The role of Smad7 in oral mucositis
Protein & Cell (2015)
-
Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression
Molecular Cancer (2011)
-
Unraveling the biological functions of Smad7 with mouse models
Cell & Bioscience (2011)
-
Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions
Modern Pathology (2010)