MicroRNA-driven regulation of immunosuppressive microenvironment in hepatocellular carcinoma.

Authors

Gerard J Nuovo, Thomas C Heineman, Esmerina Tili, Carlo M Croce

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 40. Pages e2618249123. Oct 06, 2026. Epub Sep 28, 2026.

Abstract

We investigated the role of tumor microenvironment (TME) in evolution of liver cirrhosis to hepatocellular carcinoma (HCC). Nonmalignant hepatic tissues, including chronic hepatitis and cirrhosis, retained expression of liver specific miR-122 and hepatocyte nuclear factor 4 (HNF-4) transcription factor and exhibited an immune surveillance program characterized by Inducible T cell Costimulatory Ligand (ICOSL) and NF-κB expression, low Suppressor of Cytokine Signaling 1 (SOCS1) levels, and abundant cytotoxic T cell infiltration. In contrast, progression to HCC was associated with loss of cytotoxic T cells, loss of ICOSL, PDL1, HNF-4, SMAD7, and NF-κB expression, and marked upregulation of YAP1 oncogene. TGF-β overexpression was induced by SMAD7 loss, mediated by miR-21 upregulation. Loss of HNF4, was associated with reduced miR-122 expression and subsequent upregulation of its target, SOCS1. Chronic inflammation, driven by miR-155, created an immune permissive environment that facilitated miR-21 induction and miR-122 loss. In addition, miR-21 and miR-155 contributed to malignant transformation through suppression of numerous tumor suppressor genes and enhanced YAP1 expression, a potent hepatocyte oncogene. These findings were recapitulated in orthotopic HCC mouse models, which demonstrated loss of ICOSL, PDL1, and HNF4 expression, minimal cytotoxic T cell infiltration, and increased of SOCS1, YAP1, and TGF-β expression. It is concluded that the transition from cirrhosis to HCC is associated by coordinated immunosuppression and oncogenic signaling driven by miR-21 and miR-155, together with the loss of miR-122. Targeting miR-155 may therefore represent a preventive strategy for HCC development in patients with chronic viral hepatitis.

PMID:
42804630
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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