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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 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.

SUBMITTER: Liu Q

PROVIDER: S-EPMC5283632 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.

Liu Qiuyan Q Zhu Ha H Zhang Chaoxiong C Chen Taoyong T Cao Xuetao X

Oncoimmunology 20161223 1

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, ...[more]

PMID: 28197363

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Project description:Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC.

Dataset Information

Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.

Publications

Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.

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