Journal Article

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

Mu, Shidai, Cui, Guohui, Fan, Fengjuan, Ai, Lisha, Sun, Chunyan, Qin, You, Wang, Yadan, Yan, Han, Wang, Huafang, Guo, Tao, Mei, Heng, Hu, Yu

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Angiogenesis / Animals / Antagomirs - genetics / Antagomirs - metabolism / Biomedical and Life Sciences / Biomedicine / Bone marrow / Cancer / Cancer Research / Cancer stem cells / Cell Communication / Cell Line, Tumor / Chemotherapy / Clinical outcomes / Development and progression / DNA / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA Methylation / DNA Methyltransferase 3B / Drug resistance / Female / Flow cytometry / Gene expression / Gene Expression Regulation, Neoplastic / Genes / Genetic research / Genotype & phenotype / Granulocytes - metabolism / Granulocytes - pathology / Humans / Immunology / Lymphocytes / Male / Melanoma / Methylation / Methyltransferases / Mice / Mice, Nude / Multiple myeloma / Multiple Myeloma - genetics / Multiple Myeloma - metabolism / Multiple Myeloma - mortality / Multiple Myeloma - pathology / Myeloid-derived suppressor cells / Myeloid-Derived Suppressor Cells - metabolism / Myeloid-Derived Suppressor Cells - pathology / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neoplasm Staging / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Neovascularization, Pathologic - mortality / Neovascularization, Pathologic - pathology / Oncology / Ovarian cancer / Patients / Phenotypes / piRNA / Polymerase chain reaction / Population / RNA, Small Interfering - antagonists & inhibitors / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Signal Transduction / Stem cell transplantation / Stem cells / Suppressor cells / Survival Analysis / Tumor Microenvironment - genetics / Tumors / Xenograft Model Antitumor Assays