STAT3 Activation of miR-21 and miR-181b-1 via PTEN and CYLD Are Part of the Epigenetic Switch Linking Inflammation to Cancer
Open accessAbstract
A transient inflammatory signal can initiate an epigenetic switch from nontransformed to cancer cells via a positive feedback loop involving NF-kappaB, Lin28, let-7, and IL-6. We identify differentially regulated microRNAs important for this switch and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL-6, 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-kappaB 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 IL-6 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.
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MIR21 suppresses PTEN and MIR181b-1 suppresses CYLD.
“It is reported that the STAT3 directly activates MIR21 and MIR181b-1, respectively, suppressing the targets phosphatase and tensin homolog (PTEN) and CYLD (CYLD lysine 63 deubiquitinase) tumor suppressors [83,84].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [83]
STAT3 directly activates MIR21 and MIR181b-1.
“It is reported that the STAT3 directly activates MIR21 and MIR181b-1, respectively, suppressing the targets phosphatase and tensin homolog (PTEN) and CYLD (CYLD lysine 63 deubiquitinase) tumor suppressors [83,84].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [83]
STAT3-dependent up-regulation of microRNAs (such as miR-21 and miR-181b-1) mediates repression of gene expression.
“such as those requiring STAT3-dependent up-regulation of microRNAs (such as miR-21 and miR-181b-1 [56]) that mediate repression of gene expression.”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [56]
STAT3-induced miR-21 and miR-181b-1 activate NF-κB, resulting in the induction of IL-6 gene expression.
“STAT3-induced microRNA (miR)-21 and miR-181b-1 activate NF-κB, resulting in the induction of IL-6 gene expression (90).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [90]
STAT3 activates NF-κB through the direct induction of miR-21 and miR-181b-1, leading to IL-6 gene expression.
“In addition, STAT3 activates NF-κB through the direct induction of miR-21 and miR-181b-1, leading to IL-6 gene expression (90).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [90]
Activation of Stat3, an important component of the NF-κB signaling pathway, increases miR-181 expression.
“Activation of Stat3, an important component of the NF-κB signaling pathway, has also been shown to increase miR-181 expression (Iliopoulos et al., 2010).”
From Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes (2013) · cites this paper as Iliopoulos et al., 2010
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- Authors
- Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L., & Struhl, K.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Struhl, Kevin
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 39
- Issue
- 4
- Pages
- 493-506
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2929389
- OpenAlex
- W2167715370
- Cited by
- 830
- References
- 0
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 22 · 2023: 22 · 2022: 35 · 2021: 48 · 2020: 46 · 2019: 53 · 2018: 53 · 2017: 57 · 2016: 60 · 2015: 92 · 2014: 76 · 2013: 77 · 2012: 80
- FWCI
- 22.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (R01HG003985, HG 3985)
- National Cancer Institute (R01CA107486, CA107486)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT3, miR-21, PTEN, CYLD, epigenetic switch, inflammation-associated cancer, interleukin-6, NF-κB, positive feedback loop, microRNA regulation, colon adenocarcinoma, tumor suppressor inactivation, transcription factor binding sites
- MeSH terms
- Deubiquitinating Enzyme CYLD, Adenocarcinoma, Algorithms, Animals, Binding Sites, Breast Neoplasms, Cell Movement, Cell Transformation, Neoplastic, Colonic Neoplasms, Female, Humans, Inflammation, Kinetics, Mice, Nude, Neoplasm Invasiveness, Promoter Regions, Genetic, Receptors, Estrogen, Transfection, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, NF-kappa B, Genes, src, Inflammation Mediators, HT29 Cells, Computational Biology, Xenograft Model Antitumor Assays, Tumor Suppressor Proteins, RNA Interference, MicroRNAs, Mammary Glands, Human, Epigenesis, Genetic, HCT116 Cells, Tumor Burden, Cell Proliferation, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice
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