EurekaMag.com logo
+ Site Statistics
References:
53,214,146
Abstracts:
29,074,682
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on Google+Follow on Google+
Follow on LinkedInFollow on LinkedIn

+ Translate

Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages



Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages



Cancer Research 76(6): 1403-1415



Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J-binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1α and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential.

(PDF same-day service: $19.90)

Accession: 057892454

Download citation: RISBibTeXText

PMID: 26759236

DOI: 10.1158/0008-5472.CAN-15-2019



Related references

Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). Journal of Biological Chemistry 287(48): 40140-9, 2013

Contrasting effects of activated and nonactivated macrophages and macrophages from tumor-bearing mice on tumor growth in vivo. Journal of the National Cancer Institute 65(5): 913-920, 1980

Vasoactive intestinal peptide represses activation of tumor-associated macrophages in gastric cancer via regulation of TNFα, IL-6, IL-12 and iNOS. International Journal of Oncology 47(4): 1361-1370, 2016

In human invasive breast ductal carcinoma, tumor stromal macrophages and tumor nest macrophages have distinct relationships with clinicopathological parameters and tumor angiogenesis. Virchows Archiv 462(3): 257-267, 2013

Resveratrol Prevents Tumor Growth and Metastasis by Inhibiting Lymphangiogenesis and M2 Macrophage Activation and Differentiation in Tumor-associated Macrophages. Nutrition and Cancer 68(4): 667-678, 2016

Proteomic analysis of macrophages: a potential way to identify novel proteins associated with activation of macrophages for tumor cell killing. Cellular & Molecular Immunology 4(5): 359-367, 2007

Tumor-specific bacteriophages induce tumor destruction through activation of tumor-associated macrophages. Journal of Immunology 182(5): 3105-3111, 2009

Suppression of antibody-sensitized tumor cells by macrophages: insufficient supply or activation of macrophages within large tumors. Journal of Immunology 122(2): 379-382, 1979

Prognostic Implication of M2 Macrophages Are Determined by the Proportional Balance of Tumor Associated Macrophages and Tumor Infiltrating Lymphocytes in Microsatellite-Unstable Gastric Carcinoma. Plos One 10(12): E0144192-E0144192, 2016

Expression of class II-MHC antigens by tumor-associated and peritoneal macrophages: systemic induction during tumor growth and tumor rejection. Journal of Leukocyte Biology 40(5): 499-509, 1986

Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated macrophages are two very different subpopulations. Cellular Immunology 283(1-2): 51-60, 2013

Tumor associated macrophages in the MethA tumor model Inhibition or promotion of tumor cell growth?. 9TH INTERNATIONAL CONGRESS OF IMMUNOLOGY The 9th International Congress of Immunology : 533, 1995

Tumor-associated macrophages share in vitro growth characteristics with resident but not elicited macrophages. Journal of Leukocyte Biology 50(2): 167-175, 1991

Tumor necrosis factor-related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype. Molecular Biology of the Cell 26(18): 3178-3189, 2016

Expression of class ii major histocompatibility complex antigens by tumor associated and peritoneal macrophages systemic induction during tumor growth and tumor rejection. Journal of Leukocyte Biology 40(5): 499-510, 1986