BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer Academic Article uri icon

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abstract

  • AbstractInflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.

authors

  • Conciatori, Fabiana
  • Bazzichetto, Chiara
  • Amoreo, Carla Azzurra
  • Sperduti, Isabella
  • Donzelli, Sara
  • Diodoro, Maria Grazia
  • Buglioni, Simonetta
  • Falcone, Italia
  • Shirasawa, Senji
  • Blandino, Giovanni
  • Ferretti, Gianluigi
  • Cognetti, Francesco
  • Milella, Michele
  • Ciuffreda, Ludovica

publication date

  • December 2020