Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis

Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3111-6. doi: 10.1073/pnas.0910667107. Epub 2010 Feb 1.


The mechanisms by which microRNA dysfunction contributes to the pathogenesis of diffuse large B cell lymphoma (DLBCL) are not well established. The identification of the genes and pathways directly targeted by these small regulatory RNAs is a critical step to advance this field. Using unbiased genome-wide approaches in DLBCL, we discovered that the oncogenic microRNA-155 (miR-155) directly targets the bone morphogenetic protein (BMP)-responsive transcriptional factor SMAD5. Surprisingly, we found that in DLBCL a noncanonical signaling module linking TGF-beta1 signals to SMAD5 is also active. In agreement with these data, miR-155 overexpression rendered DLBCLs resistant to the growth-inhibitory effects of both TGF-beta1 and BMPs, via defective induction of p21 and impaired cell cycle arrest. In confirmatory experiments, RNAi-based SMAD5 knockdown recapitulated in vitro and in vivo the effects miR-155 overexpression. Furthermore, in primary DLBCLs, miR-155 overexpression inhibited SMAD5 expression and disrupted its activity, as defined by individual and global analyses of its transcriptional targets. Together, our data helped explain miR-155 function, highlighted a hitherto unappreciated role of SMAD5 in lymphoma biology, and defined a unique mechanism used by cancer cells to escape TGF-beta's growth-inhibitory effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • MicroRNAs / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad5 Protein / metabolism*
  • Statistics, Nonparametric
  • Transforming Growth Factor beta / metabolism*


  • Bone Morphogenetic Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN155 microRNA, human
  • MicroRNAs
  • Smad5 Protein
  • Transforming Growth Factor beta