Skip to main content
SpringerLink
Log in

TGF-β/Smad Signalling Pathway in Cancer

  • Chapter
  • First Online:
Recent Trends in Cancer Biology: Spotlight on Signaling Cascades and microRNAs

  • 803 Accesses

Abstract

Transforming growth factor (TGF)-β signalling pathway recently received attention as putative therapeutic target in cancer therapy. TGF-β is dual functional in development of cancer. In early stages of tumour development, TGF-β plays tumour suppressive, and as tumour progressed, TGF-β is an oncogenic factor. Functioning as tumour suppressor, TGF-β is a potential growth inhibitor. Cancerous cells show high sensitivity to TGF-β inhibition either by depletion of TGF-β signalling components in genetic level or by perturbation of downstream signalling proteins in protein level. Intense investigations had revealed that Smad proteins constitute as core components of TGF-β intracellular cascades. Typical development of cancer often contains production of excess TGF-β which accelerates the invasion and metastasis as well as inhibiting the anti-tumoural immune responses. In order to design optimal approaches in cancer therapeutic regimes, comprehending the oncogenic function of TGF-β and function of its downstream proteins (Smads) are required. The approaches must be in the direction of inhibition of those TGF-β functions which induce metastasis phenotypes, but at the same time preserve its growth inhibitory effects. To date several anti-cancer drugs such as Genistein and several microRNAs such as microRNA-452, demonstrated the new insights in induction of tumour suppressive potential of TGF-β signalling pathways among various cancer types.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Roberts A, Sporn M. The transforming growth factor-βs. In: Peptide growth factors and their receptors I. New York, NY: Springer; 1990. p. 419–72.

    Google Scholar 

  2. Coffey R, et al. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol. 1988;8(8):3088–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Welch DR, Fabra A, Nakajima M. Transforming growth factor beta stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc Natl Acad Sci. 1990;87(19):7678–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Akhurst RJ, Derynck R. TGF-β signaling in cancer a double-edged sword. Trends Cell Biol. 2001;11:S44–51.

    CAS  PubMed  Google Scholar 

  5. Huminiecki L, et al. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. Evol Biol. 2009;9(1):28.

    Google Scholar 

  6. Kang Y, Chen C-R, Massagué J. A self-enabling TGFβ response coupled to stress signaling: smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003;11(4):915–26.

    Article  CAS  PubMed  Google Scholar 

  7. Padua D, et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133(1):66–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer. 2003;3(11):807–20.

    Article  CAS  PubMed  Google Scholar 

  9. Seoane J. The TGFß pathway as a therapeutic target in cancer. Clin Transl Oncol. 2008;10(1):14–9.

    Article  CAS  PubMed  Google Scholar 

  10. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. J Cell Sci. 2003;116(2):217–24.

    Article  CAS  PubMed  Google Scholar 

  11. Ten Dijke P, Arthur HM. Extracellular control of TGFβ signalling in vascular development and disease. Nat Rev Mol Cell Biol. 2007;8(11):857–69.

    Article  PubMed  CAS  Google Scholar 

  12. Lee MK, et al. TGF‐β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007;26(17):3957–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Massagué J. TGFβ in cancer. Cell. 2008;134(2):215–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.

    Article  CAS  PubMed  Google Scholar 

  15. Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19(23):2783–810.

    Article  PubMed  CAS  Google Scholar 

  16. Inman GJ, Hill CS. Stoichiometry of active smad-transcription factor complexes on DNA. J Biol Chem. 2002;277(52):51008–16.

    Article  CAS  PubMed  Google Scholar 

  17. Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Huse M, et al. The TGFβ receptor activation process: an inhibitor-to substrate-binding switch. Mol Cell. 2001;8(3):671–82.

    Article  CAS  PubMed  Google Scholar 

  19. Groppe J, et al. Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell. 2008;29(2):157–68.

    Article  CAS  PubMed  Google Scholar 

  20. Batut J, et al. Two highly related regulatory subunits of PP2A exert opposite effects on TGF-β/Activin/Nodal signalling. Development. 2008;135(17):2927–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kang JS, et al. The type I TGF-β receptor is covalently modified and regulated by sumoylation. Nat Cell Biol. 2008;10(6):654–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moustakas A, Heldin C-H. The regulation of TGFβ signal transduction. Development. 2009;136(22):3699–714.

    Article  CAS  PubMed  Google Scholar 

  23. Shi W, et al. Endofin acts as a Smad anchor for receptor activation in BMP signaling. J Cell Sci. 2007;120(7):1216–24.

    Article  CAS  PubMed  Google Scholar 

  24. Chen Y-G, et al. Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-β signaling. J Biol Chem. 2007;282(13):9688–95.

    Article  CAS  PubMed  Google Scholar 

  25. Lin H-K, Bergmann S, Pandolfi PP. Cytoplasmic PML function in TGF-β signalling. Nature. 2004;431(7005):205–11.

    Article  CAS  PubMed  Google Scholar 

  26. Choi S-C, et al. Regulation of activin/nodal signaling by Rap2-directed receptor trafficking. Dev Cell. 2008;15(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  27. Hu H, et al. Integration of transforming growth factor β and RAS signaling silences a RAB5 guanine nucleotide exchange factor and enhances growth factor-directed cell migration. Mol Cell Biol. 2008;28(5):1573–83.

    Article  CAS  PubMed  Google Scholar 

  28. Dai F, et al. Erbin inhibits transforming growth factor β signaling through a novel Smad-interacting domain. Mol Cell Biol. 2007;27(17):6183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Clarke DC, et al. Transforming growth factor β depletion is the primary determinant of Smad signaling kinetics. Mol Cell Biol. 2009;29(9):2443–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Affolter M, Basler K. The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nat Rev Genet. 2007;8(9):663–74.

    Article  CAS  PubMed  Google Scholar 

  31. Cheifetz S, et al. The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987;48(3):409–15.

    Article  CAS  PubMed  Google Scholar 

  32. Zakin L, De Robertis E. Extracellular regulation of BMP signaling. Curr Biol. 2010;20(3):R89–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zilberberg L, et al. Specificity of latent TGF‐β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J Cell Physiol. 2012;227(12):3828–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Groppe J, et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature. 2002;420(6916):636–42.

    Article  CAS  PubMed  Google Scholar 

  35. Shi M, et al. Latent TGF-[bgr] structure and activation. Nature. 2011;474(7351):343–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature. 2011;473(7347):308–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Müller P, et al. Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. Science. 2012;336(6082):721–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Wiater E, et al. Identification of distinct inhibin and transforming growth factor β-binding sites on betaglycan functional separation of betaglycan co-receptor actions. J Biol Chem. 2006;281(25):17011–22.

    Article  CAS  PubMed  Google Scholar 

  39. Schier AF. Nodal morphogens. Cold Spring Harb Perspect Biol. 2009;1(5):a003459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Marchuk DA. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr Opin Hematol. 1998;5(5):332–8.

    Article  CAS  PubMed  Google Scholar 

  41. Sekelsky JJ, et al. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995;139(3):1347–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Derynck R, et al. Nomenclature: vertebrate mediators of TGFβ family signals. Cell. 1996;87(2):173.

    Article  CAS  PubMed  Google Scholar 

  43. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425(6958):577–84.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang YE. Non-Smad pathways in TGF-β signaling. Cell Res. 2009;19(1):128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Edlund S, et al. Transforming growth factor-β–induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell. 2002;13(3):902–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu G, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science. 2000;287(5450):92–7.

    Article  CAS  PubMed  Google Scholar 

  47. Di Guglielmo GM, et al. Distinct endocytic pathways regulate TGF-β receptor signalling and turnover. Nat Cell Biol. 2003;5(5):410–21.

    Article  PubMed  CAS  Google Scholar 

  48. Le Roy C, Wrana JL. Clathrin-and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 2005;6(2):112–26.

    Article  PubMed  CAS  Google Scholar 

  49. Itoh S, ten Dijke P. Negative regulation of TGF-β receptor/Smad signal transduction. Curr Opin Cell Biol. 2007;19(2):176–84.

    Article  CAS  PubMed  Google Scholar 

  50. Glasgow E, Mishra L. Transforming growth factor-β signaling and ubiquitinators in cancer. Endocr Relat Cancer. 2008;15(1):59–72.

    Article  CAS  PubMed  Google Scholar 

  51. Murakami G, et al. Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell. 2003;14(7):2809–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kavsak P, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell. 2000;6(6):1365–75.

    Article  CAS  PubMed  Google Scholar 

  53. Itoh S, et al. Transforming growth factor β1 induces nuclear export of inhibitory Smad7. J Biol Chem. 1998;273(44):29195–201.

    Article  CAS  PubMed  Google Scholar 

  54. Tajima Y, et al. Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-β signaling by Smad7. J Biol Chem. 2003;278(12):10716–21.

    Article  CAS  PubMed  Google Scholar 

  55. Wiesner S, et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell. 2007;130(4):651–62.

    Article  CAS  PubMed  Google Scholar 

  56. Suzuki C, et al. Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem. 2002;277(42):39919–25.

    Article  CAS  PubMed  Google Scholar 

  57. Ogunjimi AA, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell. 2005;19(3):297–308.

    Article  CAS  PubMed  Google Scholar 

  58. Wrighton KH, Lin X, Feng X-H. Critical regulation of TGFβ signaling by Hsp90. Proc Natl Acad Sci. 2008;105(27):9244–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Datta PK, Moses HL. STRAP and Smad7 synergize in the inhibition of transforming growth factor β signaling. Mol Cell Biol. 2000;20(9):3157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Komuro A, et al. Negative regulation of transforming growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1). Oncogene. 2004;23(41):6914–23.

    Article  CAS  PubMed  Google Scholar 

  61. Lallemand F, et al. AIP4 restricts transforming growth factor-β signaling through a ubiquitination-independent mechanism. J Biol Chem. 2005;280(30):27645–53.

    Article  CAS  PubMed  Google Scholar 

  62. Kowanetz M, et al. TGFβ induces SIK to negatively regulate type I receptor kinase signaling. J Cell Biol. 2008;182(4):655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Su Y, et al. The evolutionally conserved activity of Dapper2 in antagonizing TGF-β signaling. Fed Am Soc Exp Biol J. 2007;21(3):682–90.

    CAS  Google Scholar 

  64. Zhu H, et al. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999;400(6745):687–93.

    Article  CAS  PubMed  Google Scholar 

  65. Lin X, Liang M, Feng X-H. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-β signaling. J Biol Chem. 2000;275(47):36818–22.

    Article  CAS  PubMed  Google Scholar 

  66. Inoue Y, et al. Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling. J Interferon Cytokine Res. 2004;24(1):43–54.

    Article  CAS  PubMed  Google Scholar 

  67. Li L, et al. CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. Mol Cell Biol. 2004;24(2):856–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Guo X, et al. Axin and GSK3-β control Smad3 protein stability and modulate TGF-β signaling. Genes Dev. 2008;22(1):106–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ross S, Hill CS. How the Smads regulate transcription. Int J Biochem Cell Biol. 2008;40(3):383–408.

    Article  CAS  PubMed  Google Scholar 

  70. Fuentealba LC, et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell. 2007;131(5):980–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-β-activated Smad2. Nat Cell Biol. 1999;1(8):472–8.

    Article  CAS  PubMed  Google Scholar 

  72. Bonni S, et al. TGF-β induces assembly of a Smad2–Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol. 2001;3(6):587–95.

    Article  CAS  PubMed  Google Scholar 

  73. Bai Y, et al. Itch E3 ligase-mediated regulation of TGF-β signaling by modulating smad2 phosphorylation. Mol Cell. 2004;15(5):825–31.

    Article  CAS  PubMed  Google Scholar 

  74. Wohlfert EA, et al. Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-β sensitivity in vitro and in vivo. J Immunol. 2006;176(3):1316–20.

    Article  CAS  PubMed  Google Scholar 

  75. Fukuchi M, et al. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol Biol Cell. 2001;12(5):1431–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mavrakis KJ, et al. Arkadia enhances Nodal/TGF-β signaling by coupling phospho-Smad2/3 activity and turnover. PLoS Biol. 2007;5(3):e67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Imoto S, et al. Regulation of transforming growth factor-β signaling by protein inhibitor of activated STAT, PIASy through Smad3. J Biol Chem. 2003;278(36):34253–8.

    Article  CAS  PubMed  Google Scholar 

  78. Wan M, et al. Smad4 protein stability is regulated by ubiquitin ligase SCFβ-TrCP1. J Biol Chem. 2004;279(15):14484–7.

    Article  CAS  PubMed  Google Scholar 

  79. Wan M, et al. Jab1 antagonizes TGF‐β signaling by inducing Smad4 degradation. EMBO Rep. 2002;3(2):171–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liang M, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2. Mol Cell Biol. 2004;24(17):7524–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Morén A, et al. Differential ubiquitination defines the functional status of the tumor suppressor Smad4. J Biol Chem. 2003;278(35):33571–82.

    Article  PubMed  Google Scholar 

  82. Lee PS, et al. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-β family signaling. J Biol Chem. 2003;278(30):27853–63.

    Article  CAS  PubMed  Google Scholar 

  83. Wang B, Suzuki H, Kato M. Roles of mono-ubiquitinated Smad4 in the formation of Smad transcriptional complexes. Biochem Biophys Res Commun. 2008;376(2):288–92.

    Article  CAS  PubMed  Google Scholar 

  84. Jianyin L, et al. Repression of Smad4 transcriptional activity by SUMO modification. Biochem J. 2004;379(1):23–9.

    Article  Google Scholar 

  85. Ebisawa T, et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276(16):12477–80.

    Article  CAS  PubMed  Google Scholar 

  86. Koinuma D, et al. Arkadia amplifies TGF‐β superfamily signalling through degradation of Smad7. EMBO J. 2003;22(24):6458–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Grönroos E, et al. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell. 2002;10(3):483–93.

    Article  PubMed  Google Scholar 

  88. Simonsson M, et al. The balance between acetylation and deacetylation controls Smad7 stability. J Biol Chem. 2005;280(23):21797–803.

    Article  CAS  PubMed  Google Scholar 

  89. Shen R, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem. 2006;281(6):3569–76.

    Article  CAS  PubMed  Google Scholar 

  90. Bai S, Cao X. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-β signaling. J Biol Chem. 2002;277(6):4176–82.

    Article  CAS  PubMed  Google Scholar 

  91. Inamitsu M, et al. Methylation of Smad6 by protein arginine N‐methyltransferase 1. Fed Eur Biochem Soc Lett. 2006;580(28-29):6603–11.

    Article  CAS  Google Scholar 

  92. Heldin C-H, Moustakas A. A new twist in Smad signaling. Dev Cell. 2006;10(6):685–6.

    Article  CAS  PubMed  Google Scholar 

  93. Lönn P, et al. PARP-1 attenuates Smad-mediated transcription. Mol Cell. 2010;40(4):521–32.

    Article  PubMed  CAS  Google Scholar 

  94. Eichhorn PJ, et al. USP15 stabilizes TGF-[beta] receptor I and promotes oncogenesis through the activation of TGF-[beta] signaling in glioblastoma. Nat Med. 2012;18(3):429–35.

    Article  CAS  PubMed  Google Scholar 

  95. Inui M, et al. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol. 2011;13(11):1368–75.

    Article  CAS  PubMed  Google Scholar 

  96. Stroschein SL, et al. Negative feedback regulation of TGF-β signaling by the SnoN oncoprotein. Science. 1999;286(5440):771–4.

    Article  CAS  PubMed  Google Scholar 

  97. Lu Z, et al. Transforming growth factor β activates Smad2 in the absence of receptor endocytosis. J Biol Chem. 2002;277(33):29363–8.

    Article  CAS  PubMed  Google Scholar 

  98. Zhang L, et al. Determining TGF-β receptor levels in the cell membrane. TGF-β Signal Method Protoc. 2016;1344:35–47.

    Article  CAS  Google Scholar 

  99. Yamashita M, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell. 2005;121(1):101–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Seo SR, et al. The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J. 2004;23(19):3780–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Shi W, et al. GADD34–PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor. J Cell Biol. 2004;164(2):291–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Valdimarsdottir G, et al. Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells. Cell Biol. 2006;7(1):16.

    Google Scholar 

  103. Xie W, et al. Alterations of smad signaling in human breast carcinoma are associated with poor outcome. Cancer Res. 2002;62(2):497–505.

    CAS  PubMed  Google Scholar 

  104. Akhurst RJ. TGF-β antagonists: why suppress a tumor suppressor? J Clin Invest. 2002;109(12):1533–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Glick AB, et al. Transforming growth factor β1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res. 1996;56(16):3645–50.

    CAS  PubMed  Google Scholar 

  106. Agarwal MK, et al. Macrophage inhibitory cytokine 1 mediates a p53-dependent protective arrest in S phase in response to starvation for DNA precursors. Proc Natl Acad Sci. 2006;103(44):16278–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Maxwell CA, et al. Targeted and nontargeted effects of ionizing radiation that impact genomic instability. Cancer Res. 2008;68(20):8304–11.

    Article  CAS  PubMed  Google Scholar 

  108. Tabatabai G, et al. Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-β-dependent HIF-1α-mediated induction of CXCL12. Brain. 2006;129(9):2426–35.

    Article  PubMed  Google Scholar 

  109. Kanamoto T, et al. Functional proteomics of transforming growth factor‐β1‐stimulated Mv1Lu epithelial cells: Rad51 as a target of TGFβ1‐dependent regulation of DNA repair. EMBO J. 2002;21(5):1219–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ewan KB, et al. Transforming growth factor-β1 mediates cellular response to DNA damage in situ. Cancer Res. 2002;62(20):5627–31.

    CAS  PubMed  Google Scholar 

  111. Kirshner J, et al. Inhibition of transforming growth factor-β1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res. 2006;66(22):10861–9.

    Article  CAS  PubMed  Google Scholar 

  112. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14(4):197–210.

    Article  CAS  Google Scholar 

  113. Savitsky K, et al. A single ataxia telangiectasia gene with a product similar to Pl-3 kinase. Science. 1995;268(5218):1749.

    Article  CAS  PubMed  Google Scholar 

  114. Whalen MK, et al. Specific ATM-mediated phosphorylation dependent on radiation quality. Radiat Res. 2008;170(3):353–64.

    Article  CAS  PubMed  Google Scholar 

  115. Wiegman EM, et al. TGFβ-1 dependent fast stimulation of ATM and p53 phosphorylation following exposure to ionizing radiation does not involve TGFβ-receptor I signalling. Radiother Oncol. 2007;83(3):289–95.

    Article  CAS  PubMed  Google Scholar 

  116. Barcellos-Hoff MH, Cucinotta FA. New tricks for an old fox: impact of TGFb on the DNA damage response and genomic stability. Sci Signal. 2014;7:re5.

    Article  PubMed  CAS  Google Scholar 

  117. Levy L, Hill CS. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol. 2005;25(18):8108–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shi X, et al. Study of interaction between Smad7 and DNA by single-molecule force spectroscopy. Biochem Biophys Res Commun. 2008;377(4):1284–7.

    Article  CAS  PubMed  Google Scholar 

  119. Cordenonsi M, et al. Links between tumor suppressors: p53 is required for TGF-β gene responses by cooperating with Smads. Cell. 2003;113(3):301–14.

    Article  CAS  PubMed  Google Scholar 

  120. Elston R, Inman GJ. Crosstalk between p53 and TGF-β Signalling. J Signal Transduct. 2012;2012:294097.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Dubrovska A, et al. TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene. 2005;24(14):2289–97.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang S, et al. TGFβ1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner. Cell Cycle. 2006;5(23):2787–95.

    Article  CAS  PubMed  Google Scholar 

  123. Park S, et al. Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair. Cell Mol Life Sci. 2015;72(3):583–96.

    Article  CAS  PubMed  Google Scholar 

  124. Wang M, Saha J, Cucinotta FA. Smad7 foci are present in micronuclei induced by heavy particle radiation. Mut Res Genet Toxicol Environ Mutagen. 2013;756(1):108–14.

    Article  CAS  Google Scholar 

  125. Kretzschmar M, Doody J, Massagu J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature. 1997;389(6651):618–22.

    Article  CAS  PubMed  Google Scholar 

  126. Nagata H, et al. Inhibition of c‐Jun NH2‐terminal kinase switches Smad3 signaling from oncogenesis to tumor‐suppression in rat hepatocellular carcinoma. Hepatology. 2009;49(6):1944–53.

    Article  CAS  PubMed  Google Scholar 

  127. Matsuura I, et al. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004;430(6996):226–31.

    Article  CAS  PubMed  Google Scholar 

  128. Lebrun J-J. The dual role of TGF in human cancer: from tumor suppression to cancer metastasis. Int Scholar Res Notice Mol Biol. 2012;2012:381428.

    Google Scholar 

  129. Seoane J, et al. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117(2):211–23.

    Article  CAS  PubMed  Google Scholar 

  130. Asanuma H, et al. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 2005;65(23):11018–25.

    Article  CAS  PubMed  Google Scholar 

  131. Shin S, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and-7. Biochemistry. 2001;40(4):1117–23.

    Article  CAS  PubMed  Google Scholar 

  132. Wang J, et al. Transforming growth factor β induces apoptosis through repressing the phosphoinositide 3-kinase/AKT/survivin pathway in colon cancer cells. Cancer Res. 2008;68(9):3152–60.

    Article  CAS  PubMed  Google Scholar 

  133. Shin I, et al. Transforming growth factor β enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell. 2001;12(11):3328–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yi JY, Shin I, Arteaga CL. Type I transforming growth factor β receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem. 2005;280(11):10870–6.

    Article  CAS  PubMed  Google Scholar 

  135. Grünert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol. 2003;4(8):657–65.

    Article  PubMed  CAS  Google Scholar 

  136. Grusch M, et al. The crosstalk of RAS with the TGF-β family during carcinoma progression and its implications for targeted cancer therapy. Curr Cancer Drug Targets. 2010;10(8):849–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Takai E, Tsukimoto M, Kojima S. TGF-β1 downregulates COX-2 expression leading to decrease of PGE2 production in human lung cancer A549 cells, which is involved in fibrotic response to TGF-β1. Plos One. 2013;8(10):e76346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Minn AJ, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436(7050):518–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mazhar D, Ang R, Waxman J. COX inhibitors and breast cancer. Br J Cancer. 2006;94(3):346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Neil JR, et al. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependent mechanisms. Carcinogenesis. 2008;29(11):2227–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhao M, et al. Mediator MED15 modulates transforming growth factor beta (TGFβ)/Smad signaling and breast cancer cell metastasis. J Mol Cell Biol. 2013;5(1):57–60.

    Article  PubMed  Google Scholar 

  142. Wakefield LM, Roberts AB. TGF-β signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12(1):22–9.

    Article  CAS  PubMed  Google Scholar 

  143. Xu J, Attisano L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin–proteasome pathway. Proc Natl Acad Sci. 2000;97(9):4820–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pardali K, Moustakas A. Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 2007;1775(1):21–62.

    CAS  PubMed  Google Scholar 

  145. Thiery JP, Chopin D. Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev. 1999;18(1):31–42.

    Article  CAS  PubMed  Google Scholar 

  146. Levy L, Hill CS. Alterations in components of the TGF-β superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2006;17(1):41–58.

    Article  CAS  PubMed  Google Scholar 

  147. Izzi L, Attisano L. Ubiquitin-dependent regulation of TGβ signaling in cancer. Neoplasia. 2006;8(8):677–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Suzuki A, et al. Identification of SMURF1 as a possible target for 7q21. 3‐22.1 amplification detected in a pancreatic cancer cell line by in‐house array‐based comparative genomic hybridization. Cancer Sci. 2008;99(5):986–94.

    Article  CAS  PubMed  Google Scholar 

  149. Fukuchi M, et al. High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Res. 2002;62(24):7162–5.

    CAS  PubMed  Google Scholar 

  150. Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev. 2007;26(3-4):587.

    Article  CAS  PubMed  Google Scholar 

  151. Halder SK, et al. Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. Cancer Res. 2006;66(12):6156–66.

    Article  CAS  PubMed  Google Scholar 

  152. Dupont S, et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell. 2005;121(1):87–99.

    Article  CAS  PubMed  Google Scholar 

  153. Sahai E, et al. Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J Cell Biol. 2007;176(1):35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhang H, Cohen SN. Smurf2 up-regulation activates telomere-dependent senescence. Genes Dev. 2004;18(24):3028–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Maurice D, et al. Loss of Smad4 Function in pancreatic tumors C-terminal Truncation leads to decreased stability. J Biol Chem. 2001;276(46):43175–81.

    Article  CAS  PubMed  Google Scholar 

  156. Lönn P, et al. Regulating the stability of TGFβ receptors and Smads. Cell Res. 2009;19(1):21–35.

    Article  PubMed  CAS  Google Scholar 

  157. Sun Y, et al. SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor β signaling. Proc Natl Acad Sci. 1999;96(22):12442–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Le Scolan E, et al. Transforming growth factor-β suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. Cancer Res. 2008;68(9):3277–85.

    Article  PubMed  CAS  Google Scholar 

  159. Levy L, et al. Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol Cell Biol. 2007;27(17):6068–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhang Y, et al. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci. 2001;98(3):974–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Morén A, et al. Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem. 2005;280(23):22115–23.

    Article  PubMed  CAS  Google Scholar 

  162. Du S, Barcellos-Hoff MH. Tumors as organs: biologically augmenting radiation therapy by inhibiting transforming growth factor β activity in carcinomas. Semin Radiat Oncol. 2013;23:242.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Hardee ME, et al. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res. 2012;72(16):4119–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhang M, et al. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 2011;71(23):7155–67.

    Article  CAS  PubMed  Google Scholar 

  165. Ma S, et al. MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2. Cancer Res. 2011;71(2):583–92.

    Article  CAS  PubMed  Google Scholar 

  166. Shi X-B, Tepper CG, deVere White RW. Cancerous miRNAs and their regulation. Cell Cycle. 2008;7(11):1529–38.

    Article  CAS  PubMed  Google Scholar 

  167. Guo L, et al. MicroRNAs, TGF-β signaling, and the inflammatory microenvironment in cancer. Tumor Biol. 2016;37(1):115–25.

    Article  CAS  Google Scholar 

  168. Goto Y, et al. Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer. Br J Cancer. 2016;114:1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wang W, et al. MicroRNA-497 inhibition of ovarian cancer cell migration and invasion through targeting of SMAD specific E3 ubiquitin protein ligase 1. Biochem Biophys Res Commun. 2014;449(4):432–7.

    Article  CAS  PubMed  Google Scholar 

  170. Yu J, et al. MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nat Commun. 2016;7:13884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mishra S, et al. Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer. Oncogene. 2014;33(31):4097–106.

    Article  CAS  PubMed  Google Scholar 

  172. Xia H, Ooi LLP, 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(2):629–41.

    Article  CAS  PubMed  Google Scholar 

  173. Jiang F, et al. The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. PloS One. 2014;9(5):e96698.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Bai WD, et al. MiR-200c suppresses TGF-β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer. Int J Canc. 2014;135(6):1356–68.

    Article  CAS  Google Scholar 

  175. Yang H, et al. MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor β receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma. Hepatology. 2013;58(1):205–17.

    Article  CAS  PubMed  Google Scholar 

  176. Li Q, et al. MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7. Cancer Lett. 2013;335(1):168–74.

    Article  CAS  PubMed  Google Scholar 

  177. Keklikoglou I, et al. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways. Oncogene. 2012;31(37):4150–63.

    Article  CAS  PubMed  Google Scholar 

  178. Cai J, et al. miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer. Cancer Res. 2013;73(17):5402–15.

    Article  CAS  PubMed  Google Scholar 

  179. Gregory PA, et al. An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelialmesenchymal transition. Mol Biol Cell. 2011;22(10):1686–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Zeng Y, et al. Repression of Smad4 by miR-205 moderates TGF-β-induced epithelial-mesenchymal transition in A549 cell lines. Int J Oncol. 2016;49(2):700–8.

    Article  CAS  PubMed  Google Scholar 

  181. Ji H, et al. Inhibition of transforming growth factor beta/SMAD signal by MiR-155 is involved in arsenic trioxide-induced anti-angiogenesis in prostate cancer. Cancer Sci. 2014;105(12):1541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhang R, et al. Upregulation of microRNA-574-3p in a human gastric cancer cell line AGS by TGF-β1. Gene. 2017;605:63.

    Article  CAS  PubMed  Google Scholar 

  183. Chiyomaru T, et al. Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer. Plos One. 2013;8(3):e58929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Blahna MT, Hata A. Smad-mediated regulation of microRNA biosynthesis. Fed Eur Biochem Soc Lett. 2012;586(14):1906–12.

    Article  CAS  Google Scholar 

  185. Butz H, et al. Crosstalk between TGF-β signaling and the microRNA machinery. Trends Pharmacol Sci. 2012;33(7):382–93.

    Article  CAS  PubMed  Google Scholar 

  186. McDonald RA, et al. MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling. Cardiovasc Res. 2011;93:594.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Wang B, et al. miR-200a prevents renal fibrogenesis through repression of TGF-β2 expression. Diabetes. 2011;60(1):280–7.

    Article  CAS  PubMed  Google Scholar 

  188. Davis-Dusenbery BN, et al. Down-regulation of Krüppel-like Factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-β and bone morphogenetic protein 4. J Biol Chem. 2011;286(32):28097–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hata A, Davis BN. Control of microRNA biogenesis by TGFβ signaling pathway—a novel role of Smads in the nucleus. Cytokine Growth Factor Rev. 2009;20(5):517–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Davis BN, et al. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell. 2010;39(3):373–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Hasanpourghadi M, et al. Targeting of tubulin polymerization and induction of mitotic blockage by Methyl 2-(5-fluoro-2-hydroxyphenyl)-1 Hbenzo [d] imidazole-5-carboxylate (MBIC) in human cervical cancer HeLa cell. J Exp Clin Cancer Res. 2016;35(1):1.

    Article  CAS  Google Scholar 

  192. Hasanpourghadi M, et al. Mechanisms of the anti-tumor activity of Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1 H-benzo[d]imidazole-5-carboxylate against breast cancer in vitro and in vivo. Oncotarget. 2017;8:28840.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Hasanpourghadi M, et al. Phytometabolites targeting warburg effect in cancer cells: a mechanistic review. Curr Drug Targets. 2017;18:1086.

    Article  CAS  PubMed  Google Scholar 

  194. Ganai AA, et al. Genistein modulates the expression of NF-κB and MAPK (p-38 and ERK1/2), thereby attenuating d-Galactosamine induced fulminant hepatic failure in Wistar rats. Toxicol Appl Pharmacol. 2015;283(2):139–46.

    Article  CAS  PubMed  Google Scholar 

  195. Vassilev LT, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844–8.

    Article  CAS  PubMed  Google Scholar 

  196. Wu Y, et al. Nutlin-3 inhibits epithelial–mesenchymal transition by interfering with canonical transforming growth factor-β1-Smad-Snail/Slug axis. Cancer Lett. 2014;342(1):82–91.

    Article  CAS  PubMed  Google Scholar 

  197. Da C, et al. Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway. Oncol Rep. 2016;35(5):2767–74.

    Article  CAS  PubMed  Google Scholar 

  198. Mock CD, Jordan BC, Selvam C. Recent advances of curcumin and its analogues in breast cancer prevention and treatment. R Soc Chem Adv. 2015;5(92):75575–88.

    CAS  Google Scholar 

  199. Balta C, et al. Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway. Chem Biol Interact. 2015;240:94–101.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Mohadeseh Hasanpourghadi & Mohd. Rais Mustafa

Authors
  1. Mohadeseh Hasanpourghadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohd. Rais Mustafa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohd. Rais Mustafa .

Editor information

Editors and Affiliations

  1. Department of Biochemistry, Rashid Latif Medical College (RLMC), Lahore, Pakistan

    Sundas Fayyaz

  2. Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan

    Ammad Ahmad Farooqi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hasanpourghadi, M., Mustafa, M.R. (2018). TGF-β/Smad Signalling Pathway in Cancer. In: Fayyaz, S., Farooqi, A. (eds) Recent Trends in Cancer Biology: Spotlight on Signaling Cascades and microRNAs. Springer, Cham. https://doi.org/10.1007/978-3-319-71553-7_9

Download citation

Publish with us

Policies and ethics

Search

Navigation