Mechanism Of MiR-449c Affecting Mo-MDSC Recruitment Under Tumor Conditions

Myeloid-derived immunosuppressive cells(MDSC)are a type of heterogeneous cell population with significant immunosuppressive activity.They help tumor formation or metastasis by directly suppressing the function of immune cells,participating in the construction of the tumor microenvironment,and promoting the formation of blood vessels.According to the different cell surface markers,MDSC are divided into two subtypes,namely single-core MDSC(mo-MDSC)and granular-like MDSC(G-MDSC).Studies have shown that mo-MDSC has more prominent immunosuppressive activity than G-MDSC.Therefore,we focus on the abnormal expansion of mo-MDSC in the tumor environment.More and more studies have found that miRNA can also promote the abnormal expansion of MDSC in the tumor environment,but the specific mechanism involved in this process is unclear.According to our previous research,tumor-conditioned cellsecreted factors activate the CXCR2 receptor of myeloid-derived progenitor cells,resulting in increased mo-MDSC differentiation.During this process,miR-449 c expression increased.Based on this,this paper explored in depth the effects of miR-449 c on the accumulation of mo-MDSC under tumor-bearing conditions,and the specific mechanism of its influence on the abnormal differentiation of myeloid progenitor cells into mo-MDSC.In this paper,we injected mice with B16F10 cells to simulate tumor-bearing conditions,and used experimental techniques such as qPCR,Western blot,flow cytometry,luciferase dual reporting technology,and mouse bone marrow cells in vitro to explore the effects of tumor loading and the releated mechanisms of miRNA in moMDSC accumulation under tumor conditions.The main results are as follows:(1)The activation of CXCR2 receptor under tumor-bearing conditions changed the expression of several miRNAs,among which the expression of miR-449 c was significantly increased;(2)By in vitro condition induction technology,flow cytometry and qPCR technology,we determined that miR-449 c increase the proportion of mo-MDSC under tumor-bearing conditions;(3)By in vitro condition induction technology and flow cytometry,we determined that miR-449 c does not affect the proliferation,apoptosis and downstream differentiation of mo-MDSC,indicating that miR-449 c increases the accumulation of mo-MDSC by increasing the differentiation of progenitor cells into mo-MDSC;(4)It was further confirmed by luciferase dual-reporter technology,qPCR technology and Western blot technology that miR-449 c promoted the differentiation of myeloid progenitor cells to mo-MDSC by inhibiting the expression of STAT6 mRNA.This paper proposes a new molecular mechanism of increasing the differentiation of myeloid progenitor cells into mo-MDSC.That is the increased inflammation factors CXCL1 and CXCL2 activate the receptor CXCR2 under tumor-bearing conditions,and the activated receptors increase the expression of miR-449 c.And miR-449 c promotes the accumulation of mo-MDSC by degrading STAT6 mRNA.The results of this thesis have revealed the relationship between miRNA and abnormal accumulation of moMDSC,which may provide new targets for inhibiting tumor growth.