In:
Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 3 ( 2019-09), p. 851-870
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0270-9139
,
1527-3350
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
1472120-X