MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages
Jihane Khalife, Jayeeta Ghose, Marianna Martella, Domenico Viola, Alberto Rocci, Estelle Troadec, Cesar Terrazas, Abhay R Satoskar, Emine Gulsen Gunes, Ada Dona, James F Sanchez, P Leif Bergsagel, Marta Chesi, Alex Pozhitkov, Steven Rosen, Guido Marcucci, Jonathan J Keats, Craig C Hofmeister, Amrita Krishnan, Enrico Caserta, Flavia Pichiorri, Jihane Khalife, Jayeeta Ghose, Marianna Martella, Domenico Viola, Alberto Rocci, Estelle Troadec, Cesar Terrazas, Abhay R Satoskar, Emine Gulsen Gunes, Ada Dona, James F Sanchez, P Leif Bergsagel, Marta Chesi, Alex Pozhitkov, Steven Rosen, Guido Marcucci, Jonathan J Keats, Craig C Hofmeister, Amrita Krishnan, Enrico Caserta, Flavia Pichiorri
Abstract
High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.
Trial registration: ClinicalTrials.gov NCT01408225.
Keywords: Bone marrow; Cancer; Hematology; Macrophages; Oncology.
Conflict of interest statement
Conflict of interest: The authors have declared that no conflict of interest exists.
Figures
![Figure 1. EVs and intracellular miR-16 levels…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g131.jpg)
![Figure 2. MiR-16 is downregulated in the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g132.jpg)
![Figure 3. Extracellular miR-16 impairs MM-EV–induced M2-MΦ.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g133.jpg)
![Figure 4. EV isolated from MM cells…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g134.jpg)
![Figure 5. Evaluation of MΦ polarization in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g135.jpg)
![Figure 6. MiR-16 directly regulates the expression…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g136.jpg)
![Figure 7. 36.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g137.jpg)
![Figure 8. Illustrative diagram showing plasma cells…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6948777/bin/jciinsight-4-129348-g138.jpg)
Source: PubMed