Cited by 451Extracellular vesicles in diseaseCancer Immunotherapy and BiomarkersEndoplasmic Reticulum Stress and Disease

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Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

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Liu, Jiatao, Fan, Lulu, Yu, Hanqing, Zhang, Ju, He, Yong, Feng, Dechun, Wang, Fang, Li, Xiaoqiu, Liu, Qingqing, Li, Yuhuan, Guo, Zhenli, Gao, Bin, Wei, Wei, Wang, Hua, Sun, Guoping·2019·Hepatology

DOI 10.1002/hep.30607PMC PMC6597282

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Abstract

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68 + macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages in vitro and in vivo . Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8 + T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis in vitro . Conclusion : ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

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Authors: Liu, J., Fan, L., Yu, H., Zhang, J., He, Y., Feng, D., Wang, F., Li, X., Liu, Q., Li, Y., Guo, Z., Gao, B., Wei, W., Wang, H., & Sun, G.
Affiliations: First Affiliated Hospital of Anhui Medical University (CN)
National Institutes of Health (US)
Anhui Medical University (CN)
Corresponding author: Wang, Hua
Sun, Guoping
ORCID: Liu, Jiatao
Fan, Lulu
Yu, Hanqing
Zhang, Ju
He, Yong
Feng, Dechun
Wang, Fang
Li, Xiaoqiu
Liu, Qingqing
Li, Yuhuan
Guo, Zhenli
Gao, Bin
Wei, Wei
Wang, Hua
Sun, Guoping
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2019-04-25
Volume: 70
Issue: 1
Pages: 241-258
ISSN: 0270-9139 (ISSN-L)
1527-3350
DOI: 10.1002/hep.30607
PMC: PMC6597282
OpenAlex: W2922474621
Cited by: 449
References: 48
Citations by year: 2026: 32 · 2025: 55 · 2024: 71 · 2023: 68 · 2022: 86 · 2021: 69 · 2020: 56 · 2019: 12
FWCI: 18.44
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Natural Science Foundation of China (81372577, 81522009, 81770588, 81872047, 81602115, 81572430)
National Institutes of Health
Natural Science Foundation of Anhui Province (1608085QH195)
National Institute on Alcohol Abuse and Alcoholism (ZIAAA000368, AA000369, Z01AA000368, Z01AA000369, AA000368, ZIAAA000369)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords: endoplasmic reticulum stress, hepatocellular carcinoma, exosomes, miR-23a-3p, PD-L1, tumor-associated macrophages, tumor immunosuppression, PTEN/AKT signaling, CD8+ T cells, tunicamycin, tumor microenvironment
MeSH terms: China, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Macrophages, T-Lymphocytes, MicroRNAs, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Exosomes, Endoplasmic Reticulum Stress, B7-H1 Antigen

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Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

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