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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
Open accessAbstract
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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“Abundant expression of miR-23a-3p was found in the exosomes of HCC cells treated with tetracycline, resulting in inhibition of PTEN mRNA level.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [77]
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“The exosomes can effectively transmit the regulatory effects of miR-23 as a channel.”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [77]
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“Subsequently, it enhances the expression of phosphorylated AKT and PD-L1 in macrophages and inhibits T cell function by functioning on the miR-23a-PTEN-AKT pathway [77].”
From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [77]
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Macrophage Diversity Enhances Tumor Progression and Metastasis
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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
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Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
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From endoplasmic-reticulum stress to the inflammatory response
Zhang, K., & Kaufman, R. J. (2008) · Nature · doi:10.1038/nature07203 · Cited by 2,010
Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis
Zhou, W., Fong, M. Y., Min, Y., Somlo, G., Liu, L., Palomares, M. R., Yu, Y., Chow, A., O’Connor, S. T. F., Chin, A. R., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.007 · Cited by 1,476 · cited 2×
“(26,27) For example, metastatic breast cancer cell–secreted exosomes transfer miR-105 to endothelial cells and promote tumor cell metastasis by destroying tight junctions and the integrity of endothelial monolayers.(28) Furthermore, exosomes derived from HCC cells can transfer specific miRNAs to enhance recipient cell…”
MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response
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Regulatory mechanisms of PD-1/PD-L1 in cancers
Lin, X., Kang, K., Chen, P., Zeng, Z., Li, G., Xiong, W., Yi, M., & Xiang, B. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02023-w · Cited by 909
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Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01027-5 · Cited by 681
Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer
Zhang, H., Dai, Z., Wu, W., Wang, Z., Zhang, N., Zhang, L., Zeng, W., Liu, Z., & Cheng, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01987-7 · Cited by 551
Isolation and characterization of exosomes for cancer research
Zhu, L., Sun, H., Wang, S., Huang, S., Zheng, Y., Wang, C., Hu, B., Qin, W., Zou, T., Fu, Y., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00987-y · Cited by 537
Metadata
- 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
- Venue
- Hepatology
- Published
- 2019-04-25
- Volume
- 70
- Issue
- 1
- Pages
- 241-258
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- 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
- 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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