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IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis
Open accessAbstract
Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelial-to-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.
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“IL-6 has been previously identified as a key cytokine that directly induces tumuor growth in CRC via STAT3 activation in IECs.12,15,46,47.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [47]
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Metadata
- Authors
- Rokavec, M., Öner, M. G., Li, H., Jackstadt, R., Jiang, L., Lodygin, D., Kaller, M., Horst, D., Ziegler, P. K., Schwitalla, S., Slotta-Huspenina, J., Bader, F. G., Greten, F. R., & Hermeking, H.
- Affiliations
- TUM Klinikum (DE)
- Pathologisches Institut (DE)
- Universitätsmedizin Göttingen (DE)
- German Cancer Research Center (DE)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-03-18
- Volume
- 124
- Issue
- 4
- Pages
- 1853-1867
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3973098
- OpenAlex
- W2104268053
- Cited by
- 753
- References
- 66
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 60 · 2023: 66 · 2022: 90 · 2021: 69 · 2020: 66 · 2019: 76 · 2018: 59 · 2017: 69 · 2016: 65 · 2015: 66 · 2014: 20
- FWCI
- 23.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- GRO (submittedVersion)
- Funders
- Johns Hopkins University (HCT116)
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Deutschen Konsortium für Translationale Krebsforschung
- FP7 Ideas: European Research Council (281967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- colorectal cancer, epithelial-mesenchymal transition, interleukin-6, IL-6 receptor, STAT3, miR-34a, feedback loops, tumor invasion, metastasis, p53, snails, microRNA regulation
- MeSH terms
- Snail Family Transcription Factors, Animals, Disease Models, Animal, Female, Humans, Male, Neoplasm Invasiveness, Neoplasm Metastasis, Transcription Factors, Colorectal Neoplasms, Mice, Knockout, Receptors, Interleukin-6, Feedback, Physiological, MicroRNAs, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Epithelial-Mesenchymal Transition
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