【摘 要】
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The Notch signaling pathway has been demonstrated to play critical roles during development by specifying cell fates.In this study, we show that Notch signa
【机 构】
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DepartmentofMedicalGeneticsandDevelopmentalBiologyFourthMilitaryMedicalUniversity,Chang-LeXiStreet＃1
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The Notch signaling pathway has been demonstrated to play critical roles during development by specifying cell fates.In this study, we show that Notch signal is critically involved in the regulation of macrophage activation in tumor-associated macrophages (TAMs).TAMs contribute greatly to hallmarks of cancer.It has recently been shown that Notch blockade arrests TAM differentiation, but the exact role and mechanisms of Notch signal in TAM function remain unclear.We show that forced Notch activation in macrophages by conditional overexpressing Notch intracellular domain (NIC) resulted in sufficient TAM differentiation, but the TAM function was abrogated, leading to repressed growth of transplanted tumors in mice.We identified miR-125a as a novel downstream molecule of Notch signaling in macrophages.Notch signal upregulated miR-125a through a RBP-J-binding site in the first intron enhancer of the Spaca6A gene that hosts miR-125a.miR-125a functioned downstream to Notch signaling to enhance M1 and suppress M2 macrophage polarization by regulating FIH1 and IRF4, respectively.Macrophages transfected with miR-125a strongly repressed tumor growth by remodeling the tumor immune microenvironment and enhancing the phagocytosis of macrophages.Finally, we identified an RYBP/YY1-mediated feedback loop by which miR-125a augmented its own expression.Taken together, our data demonstrated that, in addition to supporting TAM differentiation, Notch signaling antagonized TAM function through miR-125a, and miR-125a might be potentially employed to educate macrophages in cancer therapy.
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