Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Footnotes
  • Version history
  • Article usage
  • Citations to this article

Advertisement

Corrigendum Free access | 10.1172/JCI81340

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

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

Find articles by Rokavec, M. in: PubMed | Google Scholar

Find articles by Öner, M. in: PubMed | Google Scholar

Find articles by Li, H. in: PubMed | Google Scholar

Find articles by Jackstadt, R. in: PubMed | Google Scholar

Find articles by Jiang, L. in: PubMed | Google Scholar

Find articles by Lodygin, D. in: PubMed | Google Scholar

Find articles by Kaller, M. in: PubMed | Google Scholar

Find articles by Horst, D. in: PubMed | Google Scholar

Find articles by Ziegler, P. in: PubMed | Google Scholar

Find articles by Schwitalla, S. in: PubMed | Google Scholar

Find articles by Slotta-Huspenina, J. in: PubMed | Google Scholar

Find articles by Bader, F. in: PubMed | Google Scholar

Find articles by Greten, F. in: PubMed | Google Scholar

Find articles by Hermeking, H. in: PubMed | Google Scholar

Published March 2, 2015 - More info

Published in Volume 125, Issue 3 on March 2, 2015
J Clin Invest. 2015;125(3):1362–1362. https://doi.org/10.1172/JCI81340.
Copyright © 2015, American Society for Clinical Investigation
Published March 2, 2015 - Version history
View PDF

Related article:

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis
Matjaz Rokavec, … , Florian R. Greten, Heiko Hermeking
Matjaz Rokavec, … , Florian R. Greten, Heiko Hermeking
Research Article

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

  • Text
  • PDF
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.

Authors

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

×

Original citation: J Clin Invest. 2014;124(4):1853–1867. doi:10.1172/JCI73531.

Citation for this corrigendum: J Clin Invest. 2015;125(3):1362. doi:10.1172/JCI81340.

Following the publication of this article, the authors became aware that the epitope for the IL-6R antibody (SC-661, Santa Cruz Biotechnology Inc.) is not present in the soluble variant of IL-6R (s–IL-6R), which lacks the C-terminal domain. The authors originally designated the bands detected by SC-661 as membrane-bound IL-6R (m–IL-6R; ~70 kDa) and s–IL-6R (~50 kDa); however, the identity of the 50-kDa band is not known. Thus, no conclusions regarding s–IL-6R can be made from the data presented. Accordingly, the labels on Figures 2C, 3A, 3B, 3E, and 8D have been corrected to indicate that the 50-kDa band detected by SC-661 has not been characterized. The corrected figures appear below.

In addition, this error affected portions of the text in the Results and Discussion. The corrected sentences appear below:

Results, 4th paragraph:

Besides the membrane-bound IL-6R (m–IL-6R), we also observed a signal at 50 kDa, which represents an uncharacterized band. Densitometric quantification of IL-6R signals with normalization to β-actin showed a statistically significant decrease in m–IL-6R after DOX treatment (Supplemental Figure 3A).

Results, 5th paragraph:

Interestingly, the mesenchymal-like CRC lines SW480 and SW620 showed a more pronounced expression of m–IL-6R when compared with 5 CRC lines with epithelial traits. Furthermore, the mesenchymal lines displayed STAT3 phosphorylation, which was not detectable in the epithelial lines.

Discussion, final paragraph:

For activation of STAT3, the IL-6R requires the ligand IL-6, which allows binding to gp130. In vivo, IL-6 can be generated by tumor cells or by tumor stromal cells, such as macrophages or fibroblasts (12). The RNA used for the expression analysis of human CRC samples was isolated from nonmicrodissected tumors. Therefore, several stromal cells could have contributed to IL-6 expression. The analysis of human CRC samples suggests that the IL-6R/STAT3/miR-34a loop is also manifest in primary human colorectal tumors with mesenchymal characteristics and might represent a useful prognostic marker for cancer progression. In line with these findings, we recently showed that the loss of miR-34a expression by epigenetic silencing in primary tumors is associated with increased lymph node infiltration and metastasis in colon cancer patients (57). Besides STAT3 and IL-6R, which are already established targets for cancer treatment, our results suggest that restoring miR-34a function using mimetics may have therapeutic potential for the treatment of invasive CRCs. Furthermore, recombinant, soluble gp130 may be suitable for the treatment of invasive CRC displaying MIR34A inactivation and therefore upregulation of IL-6R expression.

Finally, the following information in the supplemental data file has been corrected: (a) findings related to the quantification of soluble IL-6R protein expression have been removed, (b) the β-actin antibody utilized has been specified as Sigma-Aldrich (A2066), and (c) the unedited image for the β-actin blot corresponding to the p53 blot in Supplemental Figure 5A has been provided.

The authors regret the errors.

Footnotes

See the related article beginning on page 1853.

Version history
  • Version 1 (March 2, 2015): No description

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Footnotes
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts