An epigenetic switch involving NF-κB, Lin28, let-7 microRNA, and IL6 links inflammation to cell transformation

By D. Iliopoulos, Heather A. Hirsch, Kevin Struhl. Cell, 2009

1,316 citations recorded by the source corpus.

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 that maintains the epigenetic transformed state for many generations in the absence of the inducing signal.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e1d375937e28317bc1719df7b65af88643467711

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Citations in the corpus

Oncogenic Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms (2011, methodology): “breast epithelial cells become transformed 36 hr post-tamoxifen (TAM) treatment (Iliopoulos et al., 2009).”
Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression (2011, background): “The IL-6 in this tumor model served to further activate NF-κB, causing a positive feedback loop of inflammation and tumorigenesis (25).”
MicroRNA sponges: progress and possibilities. (2010, background): “Sustained, systemic phenotypes may result from transient miRNA perturbation in a subset of cells if secreted cytokines operate in a positive feedback loop, as in the recently described inflammatory cascade driven by IL6, let-7 down-regulation, and NF-kB (Iliopoulos et al. 2009).”
Antioxidant mechanism of tea polyphenols and its impact on health benefits (2020, background): “NF-kB NF-kB is an important transcription factor whose primary function is to regulate the expression of anti-apoptotic genes and activate certain proinflammatory cytokine and chemokines (Iliopoulos et al., 2009).”
microRNA regulation of inflammatory responses. (2012, background): “Both miR-125b and let7 are downregulated by LPS stimulation of macrophages; miR-125b targets TNF-α mRNA, whereas let-7 targets IL-6 mRNA (42, 43).”
IL-6 in inflammation, autoimmunity and cancer (2020, background): “Lin 28 induced by NF-κ B activation prevents IL-6 mRNA degradation by inhibiting microRNA let-7 (89).”
microRNAs in cancer (2013, background): “Another example of miRNA looping action is the transactivation mediated by NF-κB upon LIN28B, an RNAbinding protein that accelerates the turnover of let-7 precursors (49).”
MicroRNAs in stress signaling and human disease (2012, background): “NF-kB was demonstrated to transactivate LIN28B, which encodes an RNA binding protein that blocks processing and accelerates turnover of let-7 precursors (Iliopoulos et al., 2009).”