Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6
Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6
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小 GTP 酶 RBJ 通过 IL-6 动员 MDSC 来促进癌症进展。
DOI：
10.1080/2162402x.2016.1245265
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Qiuyan;Zhu, Ha;Cao, Xuetao
RBJ在胃肠道癌中被鉴定为失调，并通过介导活性MEK 1/2的核积累和ERK 1/2的持续激活来促进肿瘤发生和进展。考虑到MEK/ERK的核积聚和组成性激活不仅直接促进肿瘤进展，而且还诱导慢性炎症，我们想知道RBJ是否以及如何通过慢性炎症损害宿主免疫监视并因此支持肿瘤进展。在这里，我们报告说，RBJ在人乳腺癌组织中的高表达与乳腺癌患者的预后不良显着相关。RBJ的强制表达在体外和体内均促进肿瘤生长和转移。此外，RBJ强制表达荷瘤小鼠的脾脏和肿瘤组织中发现了更多的免疫抑制细胞聚集，但抗肿瘤免疫细胞亚群较少。此外，强制RBJ表达通过组成性激活MEK/ERK信号通路显著促进肿瘤细胞产生促炎细胞因子IL-6。因此，RBJ敲低在体外和体内显著降低肿瘤生长和转移，同时显著降低IL-6的产生。给予抗IL-6中和抗体可减少MDSC在体内肿瘤组织中的积聚。因此，我们的研究结果表明，RBJ介导的ERK 1/2的核组成性激活导致IL-6的持续产生和MDSC募集的增加，有助于促进肿瘤生长和转移。这些结果表明RBJ参与了肿瘤免疫逃逸，可能成为抗肿瘤药物设计的潜在靶点。
RBJ has been identified to be dysregulated in gastrointestinal cancer and promotes tumorigenesis and progression by mediating nuclear accumulation of active MEK1/2 and sustained activation of ERK1/2. Considering that nuclear accumulation and constitutive activation of MEK/ERK not only promotes tumor progression directly, but also induces chronic inflammation, we wonder whether and how RBJ impairs host immune-surveillance via chronic inflammation and consequently supports tumor progression. Here, we report that higher expression of RBJ in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. The forced expression of RBJ promotes tumor growth and metastasis both in vitro and in vivo. In addition, more accumulation of immune suppressive cells but less antitumor immune cell subpopulations were found in spleen and tumor tissue derived from RBJ force-expressed tumor-bearing mice. Furthermore, forced RBJ expression significantly promotes tumor cell production of pro-inflammatory cytokine IL-6 by constitutive activating MEK/ERK signaling pathway. Accordingly, RBJ knockdown significantly decreases tumor growth and metastasis in vitro and in vivo, with markedly reduced production of IL-6. Administration of anti-IL-6 neutralizing antibody could reduce MDSCs accumulation in tumor tissue in vivo. Therefore, our results demonstrate that RBJ-mediated nuclear constitutive activation of ERK1/2 leads to persistent production of IL-6 and increase of MDSCs recruitment, contributing to promotion of tumor growth and metastasis. These results suggest that RBJ contributes to tumor immune escape, maybe serving a potential target for design of antitumor drug.