The chemokine scavenging receptor D6/ACKR2 is a target of miR-146a in thyroid cancer
نویسندگان
چکیده
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.
منابع مشابه
Characterization of conventional and atypical receptors for the chemokine CCL2 on mouse leukocytes.
Chemokine-directed leukocyte migration is crucial for effective immune and inflammatory responses. Conventional chemokine receptors (cCKRs) directly control cell movement; atypical chemokine receptors (ACKRs) regulate coexpressed cCKRs; and both cCKRs and ACKRs internalize chemokines to limit their abundance in vivo, a process referred to as scavenging. A leukocyte's migratory and chemokine-sca...
متن کاملMicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2
Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo Altered ACKR2 function has been implicated in several inflammatory disorders, including psori...
متن کاملMortality in Mice Growth, Placental Structure, and Neonatal Human Trophoblasts and Can Regulate Fetal Mediates Chemokine Scavenging by Primary Atypical Chemokine Receptor ACKR2
متن کامل
The N-terminal Region of the Atypical Chemokine Receptor ACKR2 Is a Key Determinant of Ligand Binding*
The atypical chemokine receptor, ACKR2 is a pivotal regulator of chemokine-driven inflammatory responses and works by binding, internalizing, and degrading inflammatory CC-chemokines. ACKR2 displays promiscuity of ligand binding and is capable of interacting with up to 14 different inflammatory CC-chemokines. Despite its prominent biological role, little is known about the structure/function re...
متن کاملP 90: The Role of miR-146a in Inflammatory Process of Mesial Temporal Lobe Epilepsy (MTLE): Implication for Therapy
Epilepsy is the third most common chronic brain disorder which is characterized by an enduring predisposition to generate seizures. Mesial Temporal Lobe Epilepsy (MTLE) is the most common type of refractory epilepsy. Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of MTLE. Hundreds of micro-RNAs have been found to be abnormally expressed in epilept...
متن کامل