Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice
Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice
复制标题
内质网应激传递介体 GP73 对肿瘤微环境的调节
DOI：
10.1002/hep.30549
复制
发表时间：
2019-09-01
期刊：
影响因子：
13.5
通讯作者：
Zhong, Hui
中科院分区：
文献类型：
--
作者：
Wei, Congwen;Yang, Xiaoli;Zhong, Hui
肿瘤细胞中的未折叠蛋白反应(UPR)信号激活邻近巨噬细胞中的UPR信号，通过上调UPR靶基因和促炎细胞因子而导致肿瘤促炎。然而，这种内质网(ER)压力传递的分子基础仍然很不清楚。在这里，我们确定了高尔基体蛋白73(GP73)的分泌型，它是一种高尔基体相关蛋白，对肝细胞癌(HCC)的生长和转移至关重要，是内质网应激传递所必需的。值得注意的是，内质网应激源增加了细胞内GP73的分泌。通过GRP78，分泌的GP73刺激邻近巨噬细胞的内质网应激激活，然后释放与肿瘤相关巨噬细胞()表型相关的细胞因子和趋化因子。对肝细胞癌患者的分析显示，GP73与葡萄糖调节蛋白78的表达及密度呈正相关。GP73和CD206的高表达与预后不良有关。阻断GP73可降低两种小鼠肝癌模型中TAMs的密度，抑制肿瘤生长，延长生存期。结论：我们的研究结果为细胞外GP73在内质网应激信号的放大和传递中的分子机制提供了深入的认识。
The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor-promoting inflammation by up-regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi-associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor-associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose-regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.