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Tumor exosomal miR-3473b promotes the metastatic colonization of lung cancer cells by activating the nuclear factor-κB signaling pathway of local fibroblasts

ABSTRACT: Tumor-derived exosomes are key factors that mediate the communication between tumor cells and stromal cells. In this study, we demonstrated that there was an uptake of cancer-derived exosomes by lung fibroblasts both in vivo and in vitro, leading to upregulation of inflammatory genes in fibroblasts, such as Il-6, Ccl1, Ccl2, Ccl5 and Cxcl2. Further analysis indicated that exosomal miR-3473b-mediated suppression of Nfkbid caused the inflammatory cytokine secertion in fibroblasts and further resulted in B cells accumulation in lungs. Inhibition of miR-3473b blocked inflammatory cytokine genes such as IL-6 expression in lung fibroblasts and B cell accumulation in lung. We further demonstrated that the lung metastasis areas and numbers were significantly decreased by using B cell neutralizing antibodies, suggesting B cell may play an important role in establishment of tumor promoting microenvironment for metastatic cancers cells colonization in the lung. In the present study, we showed that intercellular crosstalk occurred between cancer cells and fibroblasts via cancer-derived exosomes. Moreover, inhibition of the NF-kB activation in fibroblasts and B cells accumulation may become a potential target for the prevention and treatment of lung cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE142584 | GEO | 2019/12/25

REPOSITORIES: GEO

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Project description:Exososmes, potent intercellular communicators, are supposed to contribute to metastasis formation, which we confirmed for exosomes of the metastatic rat pancreatic adenocarcinoma line BSp73ASML that promote metastatic settlement in lymph nodes and lung of poorly metastatic BSp73ASML cells with a selective CD44v4-v7 (BSp73ASML-CD44vkd) knockdown. To define the molecular pathway(s), whereby exosomes contribute to premetastatic niche preparation, we profiled mRNA miRNA of BSp73ASMLwt and BSp73ASML-CD44vkd- exosomes and evaluated the impact on potential target cells. BSp73ASML exosomes are recovered in the draining lymph node after subcutaneous injection. In vitro, they preferentially bind and are taken-up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. BSp73ASMLwt and BSp73ASML-CD44kd exosomes contain a restricted repertoire of mRNA and miRNA, hwere the lattter differe significantly between the two lines and even more pronounced, exosomes derived thereof with a not yet explored dominance of tumor-suppressor miRNA in ASML-CD44kd cells and exosomes. Both, exosomal mRNA and miRNA are recovered in target cells and exosome-uptake is accompanied by significant changes in gene expression. We didn't observe a correlation between exosomal mRNA and changes in target cell mRNA or proteins. Instead transferred miRNA significantly affected target cell mRNA translation as demonstrated for selected, most abundant ASML exosomal miRNA besides others, miR-494 known target MAL (myelin and lymphocytes protein)/cadherin17, and miR-542-3p which targets TRAF/cadherin17. Furthermore, MMP transcription suggested to accompany cadherin17 dwon-regulation was upregulated in miR-494 or miR542-3p transfected or exosome co-cultured LnStr. Taken together, tumor exosomes target in vivo non-transformed cells in premetastatic organs. Exosome uptake induced altered target celll gene expression is strongly promoted by exosomal miRNA where we demonstrate for the first time that exosomes/exosomal miRNA from a metastasizing tumor line can modulate stroma cells from premetastatic organs. Endothelial cells lines were treated with pancreatic adenocarcinoma (AS) derived exosomes or pancreatic adenocarcinoma derived exosomes expressing tetraspanin 8. Total RNA was isolated and used to perform the Agilent gene expression microarrays. In this assay a replicate of endothelial cell lines treated with ASTspan8 were also included. Moreover, total RNA from both base line expression of endothelial cells and rat endothelial fibroblasts were also used to perfrom gene expression microarrays. RNA isolated from Rat endothelial fibroblasts treated with the exosomes derived from rat pancreatic adenocarcinoma and exosomes derived from rat pancreatic adenocarcinoma expressing tetraspanin8 were individually used to perfrom gene expression microarrays. RNA isolated from exosomes derived from rat pancreatic adenocarcinoma cell lines expressing tetraspanin were used to peform gene expresiion to see the base line expression. Another replicate were also used. RNA isolated from base line or control of rat pancreatic adenocarcinoma wild type cells and also base line RNA isolated from rat pancreatic adenocarcinoma cells lines where CD44 was knock-down.

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Tumor exosomal miR-3473b promotes the metastatic colonization of lung cancer cells by activating the nuclear factor-κB signaling pathway of local fibroblasts

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