Tumor Biology

, Volume 35, Issue 9, pp 8379–8385 | Cite as

SMAD7: a timer of tumor progression targeting TGF-β signaling

  • Lingyu Luo
  • Nianshuang Li
  • Nonghua Lv
  • Deqiang Huang


In the context of cancer, transforming growth factor β (TGF-β) is a cell growth suppressor; however, it is also a critical inducer of invasion and metastasis. SMAD is the important mediator of TGF-β signaling pathway, which includes receptor-regulated SMADs (R-SMADs), common-mediator SMADs (co-SMADs), and inhibitory SMADs (I-SMADs). I-SMADs block the activation of R-SMADs and co-SMADs and thus play important roles especially in the SMAD-dependent signaling. SMAD7 belongs to the I-SMADs. As an inhibitor of TGF-β signaling, SMAD7 is overexpressed in numerous cancer types and its abundance is positively correlated to the malignancy. Emerging evidence has revealed the switch-in-role of SMAD7 in cancer, from a TGF-β inhibiting protein at the early stages that facilitates proliferation to an enhancer of invasion at the late stages. This role change may be accompanied or elicited by the tumor microenvironment and/or somatic mutation. Hence, current knowledge suggests a tumor-favorable timer nature of SMAD7 in cancer progression. In this review, we summarized the advances and recent findings of SMAD7 and TGF-β signaling in cancer, followed by specific discussion on the possible factors that account for the functional changes of SMAD7.


SMAD7 TGF-β Timer Switch-in-role Cancer progression 



The present study was supported by Jiangxi provincial Department Science and Technology and founded by technical Support Project of Jiangxi Provincial Department of Science and Technology (2008). We also thank Dr. Zhijun Luo, Dr. Kun-He Zhang, and Dr. Xie Yong for their technological supports.

Conflicts of interest



  1. 1.
    Chin GS, Liu W, Peled Z, Lee TY, Steinbrech DS, Hsu M, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg. 2001;108:423–9. PMID: 11496185.CrossRefPubMedGoogle Scholar
  2. 2.
    Bedossa P, Peltier E, Terris B, Franco D, Poynard T. Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 1 receptors in normal, cirrhotic, and neoplastic human livers. Hepatology. 1995;21:760–6. PMID: 7875675.PubMedGoogle Scholar
  3. 3.
    Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166:1321–32. PMID: 15855634.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J. 2004;18:816–27. PMID: 15117886.CrossRefPubMedGoogle Scholar
  5. 5.
    Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massague J. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990;62:175–85. PMID: 2163767.CrossRefPubMedGoogle Scholar
  6. 6.
    Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol. 2001;3:708–14. PMID: 11483955.CrossRefPubMedGoogle Scholar
  7. 7.
    Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11:S44–51. PMID: 11684442.PubMedGoogle Scholar
  8. 8.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–4. PMID: 23372014.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110. PMID: 23344542.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang H, Wang HS, Zhou BH, Li CL, Zhang F, Wang XF, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3beta-mediated stabilization of snail in colorectal cancer. PLoS One. 2013;8:e56664. PMID: 23431386.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Wakefield LM, Hill CS. Beyond TGFbeta: roles of other TGFbeta superfamily members in cancer. Nat Rev Cancer. 2013;13:328–41. PMID: 23612460.CrossRefPubMedGoogle Scholar
  12. 12.
    Han G, Wang XJ. Roles of TGFbeta signaling Smads in squamous cell carcinoma. Cell Biosci. 2011;1:41. PMID: 22204491.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Papadimitriou E, Kardassis D, Moustakas A, Stournaras C. TGFbeta-induced early activation of the small GTPase RhoA is Smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2. Cell Physiol Biochem. 2011;28:229–38. PMID: 21865730.CrossRefPubMedGoogle Scholar
  14. 14.
    Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58:629–41. PMID: 23471579.CrossRefPubMedGoogle Scholar
  15. 15.
    Sanchez NS, Barnett JV. TGFbeta and BMP-2 regulate epicardial cell invasion via TGFbetaR3 activation of the Par6/Smurf1/RhoA pathway. Cell Signal. 2012;24:539–48. PMID: 22033038.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Liu Q, Zhang Y, Mao H, Chen W, Luo N, Zhou Q, et al. A crosstalk between the Smad and JNK signaling in the TGF-beta-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells. PLoS One. 2012;7:e32009. PMID: 22384127.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Seay U, Sedding D, Krick S, Hecker M, Seeger W, Eickelberg O. Transforming growth factor-beta-dependent growth inhibition in primary vascular smooth muscle cells is p38-dependent. J Pharmacol Exp Ther. 2005;315:1005–12. PMID: 16120811.CrossRefPubMedGoogle Scholar
  18. 18.
    Giehl K, Seidel B, Gierschik P, Adler G, Menke A. TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation. Oncogene. 2000;19:4531–41. PMID: 11002426.CrossRefPubMedGoogle Scholar
  19. 19.
    Gore AJ, Deitz SL, Palam LR, Craven KE, Korc M. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-beta to promote proliferation. J Clin Invest. 2014;124:338–52. PMID: 24334458.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84. PMID: 14534577.CrossRefPubMedGoogle Scholar
  21. 21.
    Salomon D. Transforming growth factor beta in cancer: Janus, the two-faced god. J Natl Cancer Inst. 2014;106:djt441. PMID: 24511109.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Medici D, Hay ED, Goodenough DA. Cooperation between snail and LEF-1 transcription factors is essential for TGF-beta1-induced epithelial-mesenchymal transition. Mol Biol Cell. 2006;17:1871–9. PMID: 16467384.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Naber HP, Drabsch Y, Snaar-Jagalska BE, ten Dijke P, van Laar T. Snail and Slug, key regulators of TGF-beta-induced EMT, are sufficient for the induction of single-cell invasion. Biochem Biophys Res Commun. 2013;435:58–63. PMID: 23618854.CrossRefPubMedGoogle Scholar
  24. 24.
    Dave N, Guaita-Esteruelas S, Gutarra S, Frias A, Beltran M, Peiro S, et al. Functional cooperation between Snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. J Biol Chem. 2011;286:12024–32. PMID: 21317430.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Shiota M, Zardan A, Takeuchi A, Kumano M, Beraldi E, Naito S, et al. Clusterin mediates TGF-beta-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res. 2012;72:5261–72. PMID: 22896337.CrossRefPubMedGoogle Scholar
  26. 26.
    Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006;174:175–83. PMID: 16831886.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Ding X, Wang Y, Ma X, Guo H, Yan X, Chi Q, et al. Expression of HMGA2 in bladder cancer and its association with epithelial-to-mesenchymal transition. Cell Prolif. 2014;47:146–51. PMID: 24571540.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen QK, Lee K, Radisky DC, Nelson CM. Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells. Differentiation. 2013;86(3):126–32. PMID: 23660532.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Labelle M, Schnittler HJ, Aust DE, Friedrich K, Baretton G, Vestweber D, et al. Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. Cancer Res. 2008;68:1388–97. PMID: 18316602.CrossRefPubMedGoogle Scholar
  30. 30.
    Fuxe J, Karlsson MC. TGF-beta-induced epithelial-mesenchymal transition: a link between cancer and inflammation. Semin Cancer Biol. 2012;22:455–61. PMID: 22627188.CrossRefPubMedGoogle Scholar
  31. 31.
    Singh P, Wig JD, Srinivasan R. The Smad family and its role in pancreatic cancer. Indian J Cancer. 2011;48:351–60. PMID: 21921337.CrossRefPubMedGoogle Scholar
  32. 32.
    Hanyu A, Ishidou Y, Ebisawa T, Shimanuki T, Imamura T, Miyazono K. The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling. J Cell Biol. 2001;155:1017–27. PMID: 11739411.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Denissova NG, Pouponnot C, Long J, He D, Liu F. Transforming growth factor beta-inducible independent binding of SMAD to the Smad7 promoter. Proc Natl Acad Sci U S A. 2000;97:6397–402. PMID: 10823886.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Topper JN, Cai J, Falb D, Gimbrone Jr MA. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A. 1996;93:10417–22. PMID: 8816815.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A. 1997;94:9314–9. PMID: 9256479.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73. PMID: 9215638.CrossRefPubMedGoogle Scholar
  37. 37.
    Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, et al. Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling. J Biol Chem. 2004;279:31568–74. PMID: 15148321.CrossRefPubMedGoogle Scholar
  38. 38.
    Yan X, Pan J, Xiong W, Cheng M, Sun Y, Zhang S, et al. Yin Yang 1 (YY1) synergizes with Smad7 to inhibit TGF-beta signaling in the nucleus. Sci China Life Sci. 2014;57:128–36. PMID: 24369345.CrossRefPubMedGoogle Scholar
  39. 39.
    Yan X, Chen YG. Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling. Biochem J. 2011;434:1–10. PMID: 21269274.CrossRefPubMedGoogle Scholar
  40. 40.
    Kamiya Y, Miyazono K, Miyazawa K. Smad7 inhibits transforming growth factor-beta family type i receptors through two distinct modes of interaction. J Biol Chem. 2010;285:30804–13. PMID: 20663871.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, et al. Determinants of specificity in TGF-beta signal transduction. Genes Dev. 1998;12:2144–52. PMID: 9679059.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Lo RS, Chen YG, Shi Y, Pavletich NP, Massague J. The L3 loop: a structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J. 1998;17:996–1005. PMID: 9463378.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    ten Dijke P, Miyazono K, Heldin CH. Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends Biochem Sci. 2000;25:64–70. PMID: 10664585.CrossRefPubMedGoogle Scholar
  44. 44.
    Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, et al. Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling. J Biol Chem. 2009;284:30097–104. PMID: 19758997.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Ferrigno O, Lallemand F, Verrecchia F, L’Hoste S, Camonis J, Atfi A, et al. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene. 2002;21:4879–84. PMID: 12118366.CrossRefPubMedGoogle Scholar
  46. 46.
    Guo J, Kleeff J, Zhao Y, Li J, Giese T, Esposito I, et al. Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma. Int J Mol Med. 2006;17:761–7. PMID: 16596258.PubMedGoogle Scholar
  47. 47.
    Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000;6:1365–75. PMID: 11163210.CrossRefPubMedGoogle Scholar
  48. 48.
    Inoue Y, Imamura T. Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci. 2008;99:2107–12. PMID: 18808420.CrossRefPubMedGoogle Scholar
  49. 49.
    Bizet AA, Tran-Khanh N, Saksena A, Liu K, Buschmann MD, Philip A. CD109-mediated degradation of TGF-beta receptors and inhibition of TGF-beta responses involve regulation of SMAD7 and Smurf2 localization and function. J Cell Biochem. 2012;113:238–46. PMID: 21898545.CrossRefPubMedGoogle Scholar
  50. 50.
    Kowanetz M, Lonn P, Vanlandewijck M, Kowanetz K, Heldin CH, Moustakas A. TGFbeta induces SIK to negatively regulate type I receptor kinase signaling. J Cell Biol. 2008;182:655–62. PMID: 18725536.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, et al. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene. 2004;23:6914–23. PMID: 15221015.CrossRefPubMedGoogle Scholar
  52. 52.
    Kim BC, Lee HJ, Park SH, Lee SR, Karpova TS, McNally JG, et al. Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation. Mol Cell Biol. 2004;24:2251–62. PMID: 14993265.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Liu FY, Li XZ, Peng YM, Liu H, Liu YH. Arkadia-Smad7-mediated positive regulation of TGF-beta signaling in a rat model of tubulointerstitial fibrosis. Am J Nephrol. 2007;27:176–83. PMID: 17347560.CrossRefPubMedGoogle Scholar
  54. 54.
    Liu W, Rui H, Wang J, Lin S, He Y, Chen M, et al. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006;25:1646–58. PMID: 16601693.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Zhou F, Drabsch Y, Dekker TJ, de Vinuesa AG, Li Y, Hawinkels LJ, et al. Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-beta signalling. Nat Commun. 2014;5:3388. PMID: 24584437.PubMedGoogle Scholar
  56. 56.
    Corcoran JB, McCarthy S, Griffin B, Gaffney A, Bhreathnach U, Borgeson E, et al. IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-beta1-induced fibrotic responses. Biochim Biophys Acta. 1833;2013:1969–78. PMID: 23567938.Google Scholar
  57. 57.
    Zhao Y, Thornton AM, Kinney MC, Ma CA, Spinner JJ, Fuss IJ, et al. The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor beta (TGF-beta) signaling and the development of regulatory T cells. J Biol Chem. 2011;286:40520–30. PMID: 21931165.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Chen YK, Huang AH, Cheng PH, Yang SH, Lin LM. Overexpression of Smad proteins, especially Smad7, in oral epithelial dysplasias. Clin Oral Investig. 2013;17:921–32. PMID: 22669485.CrossRefPubMedGoogle Scholar
  59. 59.
    Parikh A, Lee C, Peronne J, Marchini S, Baccarini A, Kolev V, et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition. Nat Commun. 2014;5:2977. PMID: 24394555.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Li Y, Wang H, Li J, Yue W. MiR-181c modulates the proliferation, migration, and invasion of neuroblastoma cells by targeting Smad7. Acta Biochim Biophys Sin (Shanghai). 2014;46:48–55. PMID: 24345480.CrossRefGoogle Scholar
  61. 61.
    Li Q, Zou C, Zou C, Han Z, Xiao H, Wei H, et al. MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett. 2013;335:168–74. PMID: 23435373.CrossRefPubMedGoogle Scholar
  62. 62.
    Xu FX, Su YL, Zhang H, Kong JY, Yu H, Qian BY. Prognostic implications for high expression of MiR-25 in lung adenocarcinomas of female non-smokers. Asian Pac J Cancer Prev. 2014;15:1197–203. PMID: 24606441.CrossRefPubMedGoogle Scholar
  63. 63.
    Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207:1589–97. PMID: 20643828.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC, et al. The miR-106b-25 cluster targets Smad7, activates TGF-beta signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 2012;31:5162–71. PMID: 22286770.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69. PMID: 16557279.CrossRefPubMedGoogle Scholar
  66. 66.
    Leng A, Liu T, He Y, Li Q, Zhang G. Smad4/Smad7 balance: a role of tumorigenesis in gastric cancer. Exp Mol Pathol. 2009;87:48–53. PMID: 19341727.CrossRefPubMedGoogle Scholar
  67. 67.
    Singh P, Srinivasan R, Wig JD, Radotra BD. A study of Smad4, Smad6 and Smad7 in surgically resected samples of pancreatic ductal adenocarcinoma and their correlation with clinicopathological parameters and patient survival. BMC Res Notes. 2011;4:560. PMID: 22195733.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Yan X, Liu Z, Chen Y. Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai). 2009;41:263–72. PMID: 19352540.CrossRefGoogle Scholar
  69. 69.
    Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106:djt369. PMID: 24511106.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Edlund S, Lee SY, Grimsby S, Zhang S, Aspenstrom P, Heldin CH, et al. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Mol Cell Biol. 2005;25:1475–88. PMID: 15684397.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Kim TA, Kang JM, Hyun JS, Lee B, Kim SJ, Yang ES, et al. The Smad7-Skp2 complex orchestrates Myc stability, impacting on the cytostatic effect of TGF-beta. J Cell Sci. 2014;127:411–21. PMID: 24259667.PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Huo YY, Hu YC, He XR, Wang Y, Song BQ, Zhou PK, et al. Activation of extracellular signal-regulated kinase by TGF-beta1 via TbetaRII and Smad7 dependent mechanisms in human bronchial epithelial BEP2D cells. Cell Biol Toxicol. 2007;23:113–28. PMID: 17096210.CrossRefPubMedGoogle Scholar
  73. 73.
    Emori T, Kitamura K, Okazaki K. Nuclear Smad7 overexpressed in mesenchymal cells acts as a transcriptional corepressor by interacting with HDAC-1 and E2F to regulate cell cycle. Biol Open. 2012;1:247–60. PMID: 23213415.PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Stolfi C, Marafini I, De Simone V, Pallone F, Monteleone G. The dual role of Smad7 in the control of cancer growth and metastasis. Int J Mol Sci. 2013;14(12):23774–90. PMID: 24317436.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Salot S, Gude R. MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. Eur J Cancer. 2013;49:492–9. PMID: 22841502.CrossRefPubMedGoogle Scholar
  76. 76.
    Slattery ML, Herrick J, Curtin K, Samowitz W, Wolff RK, Caan BJ, et al. Increased risk of colon cancer associated with a genetic polymorphism of SMAD7. Cancer Res. 2010;70:1479–85. PMID: 20124488.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Huang Q, Liu L, Liu CH, Shao F, Xie F, Zhang CH, et al. Expression of Smad7 in cholangiocarcinoma: prognostic significance and implications for tumor metastasis. Asian Pac J Cancer Prev. 2012;13:5161–5. PMID: 23244128.CrossRefPubMedGoogle Scholar
  78. 78.
    Montemayor-Garcia C, Hardin H, Guo Z, Larrain C, Buehler D, Asioli S, et al. The role of epithelial mesenchymal transition markers in thyroid carcinoma progression. Endocr Pathol. 2013;24:206–12. PMID: 24126800.CrossRefPubMedGoogle Scholar
  79. 79.
    Huse K, Bakkebo M, Walchli S, Oksvold MP, Hilden VI, Forfang L, et al. Role of Smad proteins in resistance to BMP-induced growth inhibition in B-cell lymphoma. PLoS One. 2012;7:e46117. PMID: 23049692.PubMedCentralCrossRefPubMedGoogle Scholar
  80. 80.
    Javelaud D, Mohammad KS, McKenna CR, Fournier P, Luciani F, Niewolna M, et al. Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res. 2007;67:2317–24. PMID: 17332363.CrossRefPubMedGoogle Scholar
  81. 81.
    Kim S, Han J, Lee SK, Koo M, Cho DH, Bae SY, et al. Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells. Cancer Lett. 2012;314:147–54. PMID: 22033246.CrossRefPubMedGoogle Scholar
  82. 82.
    Halder SK, Beauchamp RD, Datta PK. Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Exp Cell Res. 2005;307:231–46. PMID: 15922743.CrossRefPubMedGoogle Scholar
  83. 83.
    Wang J, Zhao J, Chu ES, Mok MT, Go MY, Man K, et al. Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro. J Pathol. 2013;230:441–52. PMID: 23625826.CrossRefPubMedGoogle Scholar
  84. 84.
    Halder SK, Rachakonda G, Deane NG, Datta PK. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer. 2008;99:957–65. PMID: 18781153.PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Theohari I, Giannopoulou I, Magkou C, Nomikos A, Melissaris S, Nakopoulou L. Differential effect of the expression of TGF-beta pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior. APMIS. 2012;120:92–100. PMID: 22229264.CrossRefPubMedGoogle Scholar
  86. 86.
    Ekman M, Mu Y, Lee SY, Edlund S, Kozakai T, Thakur N, et al. APC and Smad7 link TGFbeta type I receptors to the microtubule system to promote cell migration. Mol Biol Cell. 2012;23:2109–21. PMID: 22496417.PubMedCentralCrossRefPubMedGoogle Scholar
  87. 87.
    Heikkinen PT, Nummela M, Jokilehto T, Grenman R, Kahari VM, Jaakkola PM. Hypoxic conversion of SMAD7 function from an inhibitor into a promoter of cell invasion. Cancer Res. 2010;70:5984–93. PMID: 20551054.CrossRefPubMedGoogle Scholar
  88. 88.
    Yoo YG, Kong G, Lee MO. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J. 2006;25:1231–41. PMID: 16511565.PubMedCentralCrossRefPubMedGoogle Scholar
  89. 89.
    Garcia-Albeniz X, Nan H, Valeri L, Morikawa T, Kuchiba A, Phipps AI, et al. Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival. Carcinogenesis. 2013;34:292–8. PMID: 23104301.PubMedCentralCrossRefPubMedGoogle Scholar
  90. 90.
    Jiang X, Castelao JE, Vandenberg D, Carracedo A, Redondo CM, Conti DV, et al. Genetic variations in SMAD7 are associated with colorectal cancer risk in the colon cancer family registry. PLoS One. 2013;8(4):e60464. PMID: 23560096.PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Nakahata S, Yamazaki S, Nakauchi H, Morishita K. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-beta1-mediated growth suppression in adult T-cell leukemia/lymphoma. Oncogene. 2010;29:4157–69. PMID: 20514018.CrossRefPubMedGoogle Scholar
  92. 92.
    Monteleone G, Fantini MC, Onali S, Zorzi F, Sancesario G, Bernardini S, et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol Ther. 2012;20(4):870–6. PMID: 22252452.PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Zorzi F, Angelucci E, Sedda S, Pallone F, Monteleone G. Smad7 antisense oligonucleotide-based therapy for inflammatory bowel diseases. Dig Liver Dis. 2013;45(7):552–5. PMID: 23287011.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Lingyu Luo
    • 1
  • Nianshuang Li
    • 1
  • Nonghua Lv
    • 1
  • Deqiang Huang
    • 1
  1. 1.Research Institute of Digestive DiseasesThe First Affiliated Hospital of Nanchang UniversityNanchangPeople’s Republic of China

Personalised recommendations