An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation

Cell. 2009 Nov 13;139(4):693-706. doi: 10.1016/j.cell.2009.10.014. Epub 2009 Oct 29.

Abstract

Inflammation is linked clinically and epidemiologically to cancer, and NF-kappaB appears to play a causative role, but the mechanisms are poorly understood. We show that transient activation of Src oncoprotein can mediate an epigenetic switch from immortalized breast cells to a stably transformed line that forms self-renewing mammospheres that contain cancer stem cells. Src activation triggers an inflammatory response mediated by NF-kappaB that directly activates Lin28 transcription and rapidly reduces let-7 microRNA levels. Let-7 directly inhibits IL6 expression, resulting in higher levels of IL6 than achieved by NF-kappaB activation. IL6-mediated activation of the STAT3 transcription factor is necessary for transformation, and IL6 activates NF-kappaB, thereby completing a positive feedback loop. This regulatory circuit operates in other cancer cells lines, and its transcriptional signature is found in human cancer tissues. Thus, inflammation activates a positive feedback loop that maintains the epigenetic transformed state for many generations in the absence of the inducing signal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Transformed
  • Epigenesis, Genetic*
  • Feedback, Physiological
  • Genes, src
  • Humans
  • Inflammation / metabolism*
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism*
  • NF-kappa B p50 Subunit / metabolism*
  • Neoplasm Transplantation
  • RNA-Binding Proteins / metabolism*
  • Transplantation, Heterologous

Substances

  • Interleukin-6
  • LIN-28 protein, human
  • MicroRNAs
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human