An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.
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.
Iliopoulos
Dimitrios
D
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Hirsch
Heather A
HA
Struhl
Kevin
K
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D016391:Genes, src; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009368:Neoplasm Transplantation; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014183:Transplantation, Heterologous
D015850:Interleukin-6; C000715187:Lin28A protein, human; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human