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

Deepak Rai, Sang Woo Kim, Morgan R. McKeller, Patricia L.M. Dahia, Ricardo C.T. Aguiar

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

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 oncogenicmicroRNA- 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-β1 signals to SMAD5 is also active. In agreementwith these data,miR-155 overexpression renderedDLBCLs resistant tothegrowth-inhibitory effectsof both TGF-β1 andBMPs, 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 primaryDLBCLs,miR-155 overexpression inhibited SMAD5expression 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-β's growth-inhibitory effects.

Original languageEnglish (US)
Pages (from-to)3111-3116
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010

Keywords

  • B lymphocytes
  • Bone morphogenetic protein
  • Lymphoma
  • Transforming growth factor β
  • miR-155

ASJC Scopus subject areas

  • General

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