[HTML][HTML] An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation

D Iliopoulos, HA Hirsch, K Struhl - Cell, 2009 - cell.com
Cell, 2009cell.com
Inflammation is linked clinically and epidemiologically to cancer, and NF-κB 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-κB that
directly activates Lin28 transcription and rapidly reduces let-7 microRNA levels. Let-7 …
Summary
Inflammation is linked clinically and epidemiologically to cancer, and NF-κB 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-κB 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-κB activation. IL6-mediated activation of the STAT3 transcription factor is necessary for transformation, and IL6 activates NF-κB, 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.
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