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- Title
BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer.
- 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
- Abstract
Inflammation 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. Conciatori et al find that BRAF mutations and PTEN-loss promote IL-8 production in colorectal cancer cell (CRC) lines and identify a genetic-context-dependent BRAF/ERK2/CHOP molecular axis that controls IL-8 transcription. These data may assist in the identification of drugs to target CRC.
- Subjects
COLON cancer treatment; INTERLEUKIN-8; PROTEIN expression; GENETIC transcription; CHROMATIN; BIOMARKERS
- Publication
Communications Biology, 2020, Vol 3, Issue 1, pN.PAG
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-020-01263-y