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.

中文翻译：

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ER 应力传递介质 GP 73 对肿瘤微环境的调节

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导致促肿瘤炎症。然而，这种内质网 (ER) 应力传递的分子基础仍不清楚。在这里，我们鉴定了高尔基体蛋白 73 (GP73) 的分泌形式，这是一种对肝细胞癌 (HCC) 生长和转移至关重要的高尔基体相关蛋白，对于内质网应激传递是必不可少的。值得注意的是，内质网应激物增加了 GP73 的细胞分泌。通过 GRP78，分泌的 GP73 刺激邻近巨噬细胞的内质网应激激活，然后释放参与肿瘤相关巨噬细胞 (TAM) 表型的细胞因子和趋化因子。对 HCC 患者的分析显示 GP73 与葡萄糖调节蛋白 78 (GRP78) 表达和 TAM 密度呈正相关。高 GP73 和 CD206 表达与不良预后相关。GP73 的阻断降低了 TAM 的密度，抑制了肿瘤生长，并延长了两种小鼠 HCC 模型的存活率。结论：我们的研究结果提供了对细胞外 GP73 在内质网应激信号放大和传递中的分子机制的深入了解。