Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE

Original Publication: London : Nature Pub. Group

Bone Marrow Transplantation* ; Gene Expression Regulation, Neoplastic*; Carcinoma, Hepatocellular/*genetics ; Liver Neoplasms, Experimental/*genetics ; Macrophages/*metabolism ; NF-kappa B/*genetics ; Proteins/*genetics; Adaptor Proteins, Signal Transducing ; Animals ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/therapy ; Cell Movement ; Cell Proliferation ; Gene Deletion ; Kupffer Cells/metabolism ; Kupffer Cells/pathology ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms, Experimental/metabolism ; Liver Neoplasms, Experimental/pathology ; Liver Neoplasms, Experimental/therapy ; Macrophages/cytology ; Male ; Mice ; Mice, Knockout ; NF-KappaB Inhibitor alpha/genetics ; NF-KappaB Inhibitor alpha/metabolism ; NF-kappa B/metabolism ; Neoplasm Metastasis ; Proteins/metabolism ; RAW 264.7 Cells ; Signal Transduction ; Tumor Microenvironment/genetics

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2-/-) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2-/- mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2-/- macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2-/- macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.

Comment in: Cell Death Dis. 2018 Feb 20;9(3):294. (PMID: 29463798)

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0 (Adaptor Proteins, Signal Transducing)
0 (NF-kappa B)
0 (Ndr2 protein, mouse)
0 (Proteins)
139874-52-5 (NF-KappaB Inhibitor alpha)

Date Created: 20180216 Date Completed: 20190911 Latest Revision: 20191210

20221213

PMC5833557

10.1038/s41419-018-0284-8

29445150