Abstract
We have previously shown that miR-146a, a NF-κB-regulated microRNA, is strongly expressed in human specimens and cell lines derived from anaplastic thyroid carcinomas (ATC) where it mediates some of the NF-κB pro-tumorigenic functions. By using a bioinformatic analysis, we identified the chemokine scavenger receptor D6/ ACKR2 as a target of miR146a in human ATC. We found that the expression of D6/ ACKR2 was up-regulated in miR-146a-null ATC cell lines and that the 3’ UTR of D6/ ACKR2 mRNA was able to inhibit its expression in parental, but not in miR-146a-null ATC cells. Since human specimens from primary ATC showed a low expression of D6/ ACKR2 compared to normal thyroid tissues, we analyzed the effects of D6/ACKR2 over-expression in ATC cells. Different chemokines added to the conditioned medium of D6/ACKR2 over-expressing ATC cells partially failed to drive in vitro monocyte migration, and tumors derived from the injection of the same cells in nude mice showed a decreased number of infiltrating macrophages.Taken together, these results indicate that ATC cells down-regulate D6/ACKR2 expression through miR-146a activity to sustain leukocyte trafficking inside tumor microenvironment and shed light on a novel mechanism by which NF-κB indirectly inhibits the expression and the function of anti-tumorigenic gene in thyroid cancer.
Highlights
The tumor microenvironment plays a pivotal role in the establishment and further development of cancer
These results indicate that anaplastic thyroid carcinomas (ATC) cells down-regulate D6/atypical chemokine receptor 2 (ACKR2) expression through miR-146a activity to sustain leukocyte trafficking inside tumor microenvironment and shed light on a novel mechanism by which nuclear factor-kappaB (NF-κB) indirectly inhibits the expression and the function of anti-tumorigenic gene in thyroid cancer
To identify the potential targets of miR-146a in human ATC cells, we analyzed the TargetScan 7.1 database and found that the chemokine scavenging receptor D6/ACKR2 was a predicted target of miR-146a given that two adjacent sites for its binding were located between nucleotides 111-125 of D6/ACKR2 mRNA 3’untraslated region (UTR) (Figure 1A)
Summary
The tumor microenvironment plays a pivotal role in the establishment and further development of cancer. It is composed of a number of different cell types including stromal fibroblasts, endothelial cells and immune cells which synergistically with neoplastic cells deeply contribute to tumor growth and to the multiple stages of tumor progression [1]. Once activated in neoplastic cells, NFκB promotes transcription of a number of genes that on one hand contribute to the establishment of its constitutive activation by an autocrine fashion, and on the other hand allow the recruitment of inflammatory and immune cells by a paracrine fashion, thereby facilitating the activity of tumor neighbouring cells [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
