Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression.
Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression.
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小鼠 Nur77 缺陷通过促进 TNFα 分泌和降低 CSF-1R 表达加速肿瘤侵袭和转移
DOI：
10.1371/journal.pone.0171347
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Li XM;Wang JR;Shen T;Gao SS;He XS;Li JN;Yang TY;Zhang S;Gan WJ;Li JM;Wu H
Nur 77是核受体超家族的孤儿成员，在炎症和免疫中起着关键作用。然而，Nur 77在肿瘤微环境中的作用仍然难以捉摸。结果显示，与WT小鼠相比，Nur 77的缺失显著增强肿瘤转移。此外，与来自Nur 77 +/+腹腔巨噬细胞（CM 1）的条件培养基相比，来自Nur 77-/-腹腔巨噬细胞（CM 2）的条件培养基显著促进癌细胞的EMT，并且大大增强癌细胞的迁移和侵袭能力。此外，使用TNF-α阻断抗体的研究表明，促炎细胞因子TNF-α在支持CM 2诱导的EMT以驱动癌细胞迁移和侵袭中是不可或缺的。此外，我们发现Nur 77促进了Nur 77下游靶基因CSF-1 R的表达，从而增强了炎症细胞的迁移。值得注意的是，与Nur 77 +/+小鼠相比，Nur 77-/-小鼠肿瘤中炎性细胞的浸润显著消除。总之，这些结果揭示了宿主Nur 77表达在抗肿瘤免疫应答和抑制肿瘤转移中是关键的。
Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.