Cited by 754MicroRNA in disease regulationCytokine Signaling Pathways and InteractionsMechanisms of cancer metastasis

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IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

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Rokavec, Matjaz, Öner, Meryem Gülfem, Li, Huihui, Jackstadt, Rene, Jiang, Longchang, Lodygin, Dmitri, Kaller, Markus, Horst, David, Ziegler, Paul K., Schwitalla, Sarah, Slotta-Huspenina, Julia, Bader, Franz G., Greten, Florian R., Hermeking, Heiko·2014·Journal of Clinical Investigation

DOI 10.1172/jci73531PMC PMC3973098

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Abstract

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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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: Öner, Meryem Gülfem
Li, Huihui
Kaller, Markus
Horst, David
Ziegler, Paul K.
Greten, Florian R.
Hermeking, Heiko
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2014-03-18
Volume: 124
Issue: 4
Pages: 1853-1867
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci73531
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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IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

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