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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
Published March 18, 2014
Citation Information: J Clin Invest. 2014;124(4):1853-1867. https://doi.org/10.1172/JCI73531.
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Research Article

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

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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.

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

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Figure 1

IL-6 induces EMT and invasion of CRC cells through direct repression of MIR34A by STAT3.

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IL-6 induces EMT and invasion of CRC cells through direct repression of ...
(A) qPCR analysis of indicated mRNAs in DLD-1 cells treated with IL-6 for 5 days. (B) Relative invasion of DLD-1 cells transfected with indicated siRNAs for 24 hours, followed by IL-6 treatment for 72 hours. (C) Formation of lung metastases by tail-vein injection of control and IL-6–treated (5 days) DLD-1–Luc2 cells in immunocompromised mice. Representative images of luciferase signals (upper panel). Normalized photon flux (lower panel). (D) qPCR analysis of primary (pri–miR-34a) and mature (miR-34a) miR-34a expression in DLD-1 cells treated with IL-6. (E) Expression of mature miR-34a in HT-29 CRC and MCF7 BC cells after treatment with IL-6 for 72 hours. (F) Map of the human MIR34A genomic region with the indicated phylogenetically conserved STAT3-binding site. (G) ChIP analysis of STAT3 occupancy at the human MIR34A and, as a control, the acetylcholine receptor (ACHR) locus in DLD-1 cells treated with vehicle or IL-6. (H) qPCR analysis of primary miR-34a in DLD-1 cells transfected with control or STAT3 siRNAs for 24 hours and subsequently treated with IL-6 for 72 hours. (I) qPCR analysis of indicated mRNAs in indicated cells, treated with IL-6 and DOX for 5 days. (J) Relative invasion of indicated cells treated with DOX for 24 hours and subsequently with IL-6 for 72 hours. Mean values ± SD (n = 3) are provided. *P < 0.05; **P < 0.01.

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