Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization.
Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization.
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肝脏微环境中NDRG2的缺失通过调节肿瘤相关巨噬细胞极化抑制癌症肝转移
DOI：
10.1038/s41419-018-0284-8
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Li M;Lai X;Zhao Y;Zhang Y;Li M;Li D;Kong J;Zhang Y;Jing P;Li H;Qin H;Shen L;Yao L;Li J;Dou K;Zhang J
肝脏是几种类型恶性肿瘤的主要转移部位。肝脏中的肿瘤相关巨噬细胞（TAM）在转移过程中起着至关重要的作用。将促肿瘤的M2样TAM转变为M1样表型，通过吞噬和分泌抑制因子发挥肿瘤抑制功能，可能是肝癌转移治疗的潜在治疗策略。我们首先克隆了NDRG 2（N-myc下游调节基因2）并验证了其在多种实体瘤中的肿瘤抑制作用，包括结直肠癌和肝细胞癌。然而，其在肿瘤相关的肝脏微环境中的作用，特别是在TAM中，尚未得到说明。通过在野生型（WT）和Ndrg 2基因敲除（Ndrg 2-/-）小鼠中建立肝癌转移模型，我们发现肝脏微环境中肿瘤抑制因子Ndrg 2的缺失显著抑制了肝脏集落的生长。此外，这一过程伴随着Ndrg 2 −/−小鼠中更高比例的M1样TAM浸润。有趣的是，骨髓（BM）移植显示，BM衍生的巨噬细胞（BMDM），而不是肝脏驻留枯否细胞负责的抑制作用。我们进一步证明了Ndrg 2的缺失通过NF-κB途径影响TAM极化。抑制癌细胞条件培养基刺激的BMDM中IκBα磷酸化降低了Ndrg 2 −/−巨噬细胞中M1标记物的表达。最后，体外侵袭、迁移和增殖实验证实NF-κB参与了Ndrg 2 −/−巨噬细胞的肿瘤抑制功能。总的来说，我们的研究结果强调了NDRG 2在调节TAM极化中的作用及其在促进癌症肝转移中的功能。
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 clonedNDRG2(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) andNdrg2knockout (Ndrg2−/−) mice, we found that the loss of the tumor suppressorNdrg2in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration inNdrg2−/−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 ofNdrg2influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression inNdrg2−/−macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function ofNdrg2−/−macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.
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影响因子：
3.9
作者：
Skiriutė D;Steponaitis G;Vaitkienė P;Mikučiūnas M;Skauminas K;Tamašauskas A;Kazlauskas A
通讯作者：
Kazlauskas A
DOI：
10.1073/pnas.1002372107
发表时间：
2010-07-20
影响因子：
11.1
作者：
Kitamura, Takanori;Fujishita, Teruaki;Taketo, Makoto M.
通讯作者：
Taketo, Makoto M.
影响因子：
4
作者：
Mohr, Ashley M.;Gould, John J.;McVicker, Benita L.
通讯作者：
McVicker, Benita L.
影响因子：
25.7
作者：
Lee, Dong Gwang;Lee, Sang-Hyun;Min, Jeong-Ki
通讯作者：
Min, Jeong-Ki
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.