title: Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.
abstract: 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 bothin vitroandin 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 metastasisin vitroandin vivo, with markedly reduced production of IL-6. Administration of anti-IL-6 neutralizing antibody could reduce MDSCs accumulation in tumor tissuein 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.
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University , Shanghai, China.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University , Shanghai, China.
authors.forename: Ha
authors.identifier: 0000-0002-8589-9179
authors.initials: H
authors.lastname: Zhu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University , Shanghai, China.
authors.forename: Chaoxiong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University , Shanghai, China.
authors.forename: Taoyong
authors.initials: T
authors.lastname: Chen
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China; National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
keywords: IL-6; MDSCs; immune escape; small GTPase; tumor metastasis