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GRP78 plays an integral role in tumor cell inflammation-related migration induced by M2 macrophages

机译:GRP78在M2巨噬细胞诱导的肿瘤细胞炎症相关迁移中发挥积分作用

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摘要

Macrophages are the main immune-competent cells that infiltrate in tumors. Tumor-associated macrophages (TAMs), termed M2 macrophages, facilitate tumor progress and promote metastasis. However, M2 macrophages always display an immunosuppressive phenotype, which is not in accordance with the tumor inflammatory microenvironment and inflammation-related metastasis. In this study, we established a macrophage polarization model with human monocytes and found that the conditioned medium from M2 macrophages increased GRP78 expression in tumor cells and facilitated tumor cell migration. Mechanistically, excessive GRP78 formed a protein complex with STAT3 and JAK2 to promote STAT3 phosphorylation. Furthermore, p-STAT3 facilitated the high expression of inflammatory factors IL-beta and TNF-alpha in tumor cells, which was important in M2 macrophage-induced metastasis. The present data demonstrate that M2 macrophages elevate tumor cell GRP78 expression to trigger an inflammatory response, which further facilitates tumor metastasis. Therefore, our study not only uncovered a new cause of GRP78 overexpression in tumor cell, but also, explained the antinomy of TAMs immunosuppressive properties and inflammation-related tumor metastasis.
机译:巨噬细胞是患有肿瘤浸润的主要免疫态性细胞。肿瘤相关的巨噬细胞(TAMS)称为M2巨噬细胞,促进肿瘤进展和促进转移。然而,M2巨噬细胞总是显示免疫抑制表型,这不是根据肿瘤炎症微环境和与炎症相关的转移。在这项研究中,我们与人单核细胞建立了一种巨噬细胞偏振模型,发现来自M2巨噬细胞的调节培养基在肿瘤细胞中增加GRP78表达并促进肿瘤细胞迁移。机械地,过量的GRP78形成了与Stat3和JAK2的蛋白质复合物,以促进STAT3磷酸化。此外,P-STAT3促进了肿瘤细胞中炎性因子IL-Beta和TNF-α的高表达,这在M2巨噬细胞诱导的转移中是重要的。本数据表明M2巨噬细胞升高肿瘤细胞GRP78表达以引发炎症反应,进一步促进肿瘤转移。因此,我们的研究不仅揭示了肿瘤细胞中GRP78过表达的新原因,而且还解释了TAMS免疫抑制性能和炎症相关肿瘤转移的抗胰肿瘤。

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