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Home Science & Environment Medical Research

Scientists identify lncRNA as potential biomarker and therapeutic target for hepatocellular carcinoma

March 12, 2025
in Medical Research
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Scientists identify lncRNA as potential biomarker and therapeutic target for hepatocellular carcinoma
HDAC2-AS2 in tumor-derived extracellular vesicles inhibits CD8+ T cell function by targeting cytosolic CDK9. Credit: Yang Pengyuan’s group

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, remains one of the most aggressive malignancies. In a recent study published in Nature Communications, researchers led by Profs. Yang Pengyuan and Chen Runsheng from the Institute of Biophysics of the Chinese Academy of Sciences have uncovered a novel mechanism by which tumor-derived long noncoding RNA (lncRNA) suppresses anti-tumor immunity, providing new insights into the role of extracellular vesicles (EVs) in HCC progression.

The researchers identified HDAC2-AS2 as the most significantly differentially expressed lncRNA following TGF-β stimulation. Although its overexpression or knockdown did not impact tumor cell proliferation, it markedly promoted subcutaneous tumor growth in C57 mice.

Mechanistic studies revealed that tumor-derived HDAC2-AS2 is secreted into the tumor microenvironment via EVs. Higher levels of HDAC2-AS2 were also detected in EVs from the plasma of HCC patients.

Immune function analysis showed that HDAC2-AS2 in EVs was taken up by CD8+ T cells, where it binds to intracellular cyclin-dependent kinase 9 (CDK9), leading to a reduction in intracellular CDK9 protein levels. This, in turn, induces CD8+ T cell exhaustion and apoptosis while suppressing their cytotoxic function.

Multi-omics analysis revealed that CDK9 plays a key regulatory role in CD8+ T cell activation and cytotoxicity. Single-cell RNA sequencing data from HCC patients undergoing immune checkpoint blockade (ICB) therapy showed that CDK9 enhances CD8+ T cell function during ICB treatment.

Additionally, HCC tumors with high HDAC2-AS2 expression were found to benefit more from PD-1 antibody therapy.

This study demonstrates that in HBV-associated HCC, the lncRNA HDAC2-AS2, upregulated by the TGF-β signaling pathway, targets CDK9 in CD8+ T cells via EVs, inhibiting CD8+ T cell function and promoting tumor immune evasion.

These findings provide new potential biomarker and therapeutic targets for HBV- associated HCC. It provides critical insights into the molecular mechanisms of HCC immune evasion and opens new possibilities for precision medicine approaches.

More information:
Yanan Gao et al, HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2, Nature Communications (2025). DOI: 10.1038/s41467-025-57367-8

Provided by
Chinese Academy of Sciences


Citation:
Scientists identify lncRNA as potential biomarker and therapeutic target for hepatocellular carcinoma (2025, March 12)
retrieved 12 March 2025
from https://medicalxpress.com/news/2025-03-scientists-lncrna-potential-biomarker-therapeutic.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.




Scientists identify lncRNA as potential biomarker and therapeutic target for hepatocellular carcinoma
HDAC2-AS2 in tumor-derived extracellular vesicles inhibits CD8+ T cell function by targeting cytosolic CDK9. Credit: Yang Pengyuan’s group

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, remains one of the most aggressive malignancies. In a recent study published in Nature Communications, researchers led by Profs. Yang Pengyuan and Chen Runsheng from the Institute of Biophysics of the Chinese Academy of Sciences have uncovered a novel mechanism by which tumor-derived long noncoding RNA (lncRNA) suppresses anti-tumor immunity, providing new insights into the role of extracellular vesicles (EVs) in HCC progression.

The researchers identified HDAC2-AS2 as the most significantly differentially expressed lncRNA following TGF-β stimulation. Although its overexpression or knockdown did not impact tumor cell proliferation, it markedly promoted subcutaneous tumor growth in C57 mice.

Mechanistic studies revealed that tumor-derived HDAC2-AS2 is secreted into the tumor microenvironment via EVs. Higher levels of HDAC2-AS2 were also detected in EVs from the plasma of HCC patients.

Immune function analysis showed that HDAC2-AS2 in EVs was taken up by CD8+ T cells, where it binds to intracellular cyclin-dependent kinase 9 (CDK9), leading to a reduction in intracellular CDK9 protein levels. This, in turn, induces CD8+ T cell exhaustion and apoptosis while suppressing their cytotoxic function.

Multi-omics analysis revealed that CDK9 plays a key regulatory role in CD8+ T cell activation and cytotoxicity. Single-cell RNA sequencing data from HCC patients undergoing immune checkpoint blockade (ICB) therapy showed that CDK9 enhances CD8+ T cell function during ICB treatment.

Additionally, HCC tumors with high HDAC2-AS2 expression were found to benefit more from PD-1 antibody therapy.

This study demonstrates that in HBV-associated HCC, the lncRNA HDAC2-AS2, upregulated by the TGF-β signaling pathway, targets CDK9 in CD8+ T cells via EVs, inhibiting CD8+ T cell function and promoting tumor immune evasion.

These findings provide new potential biomarker and therapeutic targets for HBV- associated HCC. It provides critical insights into the molecular mechanisms of HCC immune evasion and opens new possibilities for precision medicine approaches.

More information:
Yanan Gao et al, HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2, Nature Communications (2025). DOI: 10.1038/s41467-025-57367-8

Provided by
Chinese Academy of Sciences


Citation:
Scientists identify lncRNA as potential biomarker and therapeutic target for hepatocellular carcinoma (2025, March 12)
retrieved 12 March 2025
from https://medicalxpress.com/news/2025-03-scientists-lncrna-potential-biomarker-therapeutic.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.



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