Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation

Abstract

Background Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. Methods The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. Results Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. Conclusion Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

Myeloid-derived suppressor cells—new and exciting players in lung cancer

“…Interestingly, it has been reported that MDSCs can regulate the biology of cancer stem cells by affecting the IL-6/STAT3 and NO/NOTCH signaling pathways [81]. MDSCs endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation [82]. However, there is currently no published study on whether MDSCs affect the stemness of LC cells.…”

PIWI-Interacting RNA-004800 Is Regulated by S1P Receptor Signaling Pathway to Keep Myeloma Cell Survival

“…In MM, the contribution of piRNA to disease pathogenesis is not well-understood. One piRNA, piRNA-823, is shown to play the role in tumor formation by effect on DNA methylation and bone marrow microenvironment (7)(8)(9). This suggests a generalizable role for piRNAs in MM pathogenesis yet few have been identified.…”

Noncoding RNAs: the shot callers in tumor immune escape

“…109 In a study of multiple myeloma, granulocyte-MDCSs increased the expression of SOX2, OCT4, and Nanog in multiple myeloma stem cells by promoting the expression of piRNA-823, which controlled tumor stemness through DNMT3B activation, thereby promoting the tumor stemness phenotype. 110 The above research results provide preliminary evidence that these ncRNAs promote the development of TIE by targeting tumor stem cell-like phenotype-related pathways and genes. By inhibiting this process, we may be able to improve resistance to immunotherapy.…”