Department of General Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China.
Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China.
Cell Mol Life Sci. 2021 Dec;78(23):7709-7732. doi: 10.1007/s00018-021-03997-2. Epub 2021 Oct 28.
This study investigated the regulation of GRP78 in tumour-associated macrophage polarization in lung cancer. First, our results showed that GRP78 was upregulated in macrophages during M2 polarization and in a conditioned medium derived from lung cancer cells. Next, we found that knocking down GRP78 in macrophages promoted M1 differentiation and suppressed M2 polarization via the Janus kinase/signal transducer and activator of transcription signalling. Moreover, conditioned medium from GRP78- or insulin-like growth factor 1-knockdown macrophages attenuated the survival, proliferation, and migration of lung cancer cells, while conditioned medium from GRP78-overexpressing macrophages had the opposite effects. Additionally, GRP78 knockdown reduced both the secretion of insulin-like growth factor 1 and the phosphorylation of the insulin-like growth factor 1 receptor. Interestingly, insulin-like growth factor 1 neutralization downregulated GRP78 and suppressed GRP78 overexpression-induced M2 polarization. Mechanistically, insulin-like growth factor 1 treatment induced the translocation of GRP78 to the plasma membrane and promoted its association with the insulin-like growth factor 1 receptor. Finally, IGF-1 blockade and knockdown as well as GRP78 knockdown in macrophages inhibited M2 macrophage-induced survival, proliferation, and migration of lung cancer cells both in vitro and in vivo.
本研究探讨了 GRP78 在肺癌相关巨噬细胞极化中的调节作用。首先，我们的结果表明，GRP78 在 M2 极化过程中的巨噬细胞中以及来自肺癌细胞的条件培养基中上调。接下来，我们发现，敲低巨噬细胞中的 GRP78 通过 Janus 激酶/信号转导和转录激活因子信号促进 M1 分化并抑制 M2 极化。此外，GRP78 或胰岛素样生长因子 1 敲低巨噬细胞的条件培养基减弱了肺癌细胞的存活、增殖和迁移，而 GRP78 过表达巨噬细胞的条件培养基则有相反的效果。此外，GRP78 敲低减少了胰岛素样生长因子 1 的分泌和胰岛素样生长因子 1 受体的磷酸化。有趣的是，胰岛素样生长因子 1 中和作用降低了 GRP78 的表达，并抑制了 GRP78 过表达诱导的 M2 极化。在机制上，胰岛素样生长因子 1 处理诱导 GRP78 向质膜易位，并促进其与胰岛素样生长因子 1 受体的结合。最后，IGF-1 阻断和敲低以及巨噬细胞中 GRP78 的敲低在体外和体内均抑制了 M2 巨噬细胞诱导的肺癌细胞的存活、增殖和迁移。
