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Inflammation mobilizes tumor cells
Date:3/19/2014

directly binding to it." As the Hermeking lab could show, expression of the IL-6 receptor is itself directly repressed by miR-34a. Therefore, loss of the microRNA leads to overproduction of the cytokine receptor. Taken together, IL-6R and miRNA-34a form a feedback loop and depending on whether miR-34a or IL-6 is present in excess, tumor-promoting genes are either repressed or activated.

The feedback loop operates in vivo

Inflammation is associated with increased secretion of IL-6. The newly characterized signal mechanism that acts between IL-6R and miR-34a via STAT3 therefore provides a functional link that helps explain how chronic inflammation facilitates the formation of metastases. "We have demonstrated the significance of this link in a mouse model system, based on the use of a miR-34a-deficient mouse strain that we had generated. In a collaboration with Professor Florian Greten (Georg-Speyer-Haus, Frankfurt/M.) we found that these mutant mice show an increased tendency to develop inflammation-induced tumors", says Hermeking. Notably, these miR-34a-deficient tumors invaded into neighbouring tissue, which was not observed in normal mice. Using cultured cells derived from human tumors of the breast and prostate gland, they confirmed that the IL6R/STAT3/miR-34a feedback loop is also activated in other tumor types. "Furthermore, analysis of tumor samples from large cohorts of colorectal cancer patients revealed that activation of the loop is associated with metastasis", Hermeking reports.

The new results show that miR-34a inactivation contributes to metastasis by activating the oncogenic IL-6R/STAT3 pathway. The discovery of this feedback mechanism also offers a number of targets for therapeutic intervention. In addition to STAT3 and IL-6, which are already targeted by a number of anti-tumor agents, the new study directs attention to the potential of miR-34a as a further focus of drug development for the treatment of meta
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Contact: Luise Dirscherl
dirscherl@lmu.de
49-892-180-2706
Ludwig-Maximilians-Universitt Mnchen
Source:Eurekalert

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