STAT3 activation of miR-21 and miR-181b-1, via PTEN and CYLD, are part of the epigenetic switch linking inflammation to cancer

By D. Iliopoulos, S. Jaeger, Heather A. Hirsch, Martha L. Bulyk, Kevin Struhl. Molecules and Cells, 2010

886 citations recorded by the source corpus.

A transient inflammatory signal can initiate an epigenetic switch from non-transformed to cancer cells via a positive feedback loop involving NF-κB, Lin28, let-7, and IL6. We identify differentially regulated microRNAs important for this switch, and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL6, directly activates miR-21 and miR-181b-1. Remarkably, transient expression of either microRNA induces the epigenetic switch. MiR-21 and miR-181b-1 respectively inhibit PTEN and CYLD tumor suppressors, leading to increased NF-κB activity required to maintain the transformed state. These STAT3-mediated regulatory circuits are required for the transformed state in diverse cell lines and tumor growth in xenografts, and their transcriptional signatures are observed in colon adenocarcinomas. Thus, STAT3 is not only a downstream target of IL6, but with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b943848120eefb5cd09691de0a3c18ab228471fa

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Citations in the corpus

IL-6 in inflammation, autoimmunity and cancer (2020, background): “STAT3-induced microRNA (miR)-21 and miR-181b-1 activate NF-κ B, resulting in the induction of IL-6 gene expression (90).”
MicroRNA regulation by RNA-binding proteins and its implications for cancer (2011, background): “This activates STAT3 and reinforces LIN28 expression, both of which can lead to a transformed state in the absence of external signal”
Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis (2019, background): “For example, STAT3 activated by IL6 directly upregulated the miR-21 and miR-181b-1, which was shown to be necessary for the epigenetic switch linking inflammation to cancer [53].”
Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. (2018, background): “[60] Pannem RR, Dorn C, Ahlqvist K, Bosserhoff AK, Hellerbrand C, Massoumi R. CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.”
Improved classification of breast cancer by analysis of genetic alterations and gene expression profiling (2011, background): “miRNAs have been shown to control various key processes in tumorigenesis, such as tumor initiation (13), metastasis (15, 16), inflammation (17), and differentiation (18) in cell lines and animal models.”
MicroRNAs: the fine-tuners of Toll-like receptor signalling (2011, background): “Higher basal levels of miRNAs in certain cell types might function as important epigenetic switches required for the functional maintenance of the cell typ”
NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma (2011, background): “In fact, data published in 2010 suggest that IL-6 is part of a procarcinogenic positive-feedback loop in which Stat3 activation upregulates miR-21 and miR-181b1, leading to downregulation of PTEN, upregulation of NF-κB and promotion of cellular transformation”