Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice

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.

The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress

“…Although ER stress has been reported in many diseases involving macrophages (obesity, atherosclerosis, neuroinflammation, arthritis, cancer, pulmonary fibrosis…), its impact on macrophage polarization remains unclear. Indeed, some authors report the induction or amplification of proinflammatory M1 type cytokines by ER stress 12,13 or an augmented M2 polarization of adipose tissue macrophages after blocking IRE1α 14 whereas a M2-like profile was observed in stressed tumor associated macrophages 15,16 and, in lung macrophages, ER stress appears to favor the M2 phenotype with profibrotic effects 17 .…”

Combined and sequential non-invasive approach to diagnosing non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease and persistently normal alanine aminotransferase levels

“…We have also tested the performance of serum GP73 levels in identifying NASH in patients with NAFLD with persistent nALT. A recent study pertaining to hepatocellular carcinoma development showed increased GP73 secretion by hepatocyte endoplasmic reticulum (ER) stress 29. In view of the recognized relevance of ER stress in NAFLD pathogenesis, it is also possible to speculate that upregulation of gene expression and increased serum levels of GP73 may also occur in NASH 30.…”

A combined and sequential non-invasive approach to diagnosing non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease and persistently normal alanine aminotransferase levels

“…A recent study pertaining to hepatocellular carcinoma development showed increased GP73 secretion by hepatocyte endoplasmic reticulum (ER) stress. [29] In view of the recognised relevance of ER stress in NAFLD pathogenesis, it is also possible to speculate that up-regulation of gene expression and increased serum levels of GP73 may also occur in NASH. [30] Additionally, it has been reported that interferon gamma (IFN-γ)…”