2. Academic Validation
  3. miR-22-Galectin-1 as an integral signaling axis in regulating metabolism and immunity in HCC

miR-22-Galectin-1 as an integral signaling axis in regulating metabolism and immunity in HCC

  • Biomark Res. 2026 Jan 15;14(1):11. doi: 10.1186/s40364-025-00838-3.
Ying Hu # 1,  Tahereh Setayesh # 1,  Prasant Kumar Jena # 2,  Yutong Ji 1,  Trenton Testerman 1,  Ruiwu Liu 3,  Tsung-Chieh Shih 3,  Xiao-Jing Wang 1,  Fu-Tong Liu 4,  Kit S Lam 3,  Yu-Jui Yvonne Wan 5
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA.
  • 2 Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA.
  • 3 Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA.
  • 4 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 5 Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA. [email protected].
  • # Contributed equally.
PMID: 41540504 DOI: 10.1186/s40364-025-00838-3
Abstract

Background: While miR-22 is a suppressor of hepatocellular carcinoma (HCC), Galectin-1 (Gal-1) serves as a HCC biomarker. Our previous studies have shown the effectiveness of miR-22 gene therapy and silencing Gal-1 as two potential novel options in treating HCC in preclinical mouse models. This study examines the significance of the miR-22-Gal-1 axis in HCC development and treatment.

Methods: The roles of miR-22 and Gal-1 in human HCC were analyzed using the Cancer Genome Atlas database based on their expression levels. The temporal effects of miR-22 were studied by analyzing signaling pathways affected by miR-22 expression levels during HCC progression. AAV8-miR-22, AAV9-Gal-1 siRNA, and LLS30, a Gal-1 inhibitor, were used to treat orthotopic mouse HCC. Spatial transcriptomics established the location-specific effects of miR-22 in mouse HCC. The signaling pathways affected by miR-22 and Gal-1 were identified by analyzing human HCC transcriptomics compared with those found in miR-22, Gal-1 siRNA, or LLS30-treated mouse HCC.

Results: In the early stages of HCC, miR-22-high HCC exhibited extensive upregulation of endobiotic metabolism and xenobiotic detoxification signaling, accompanied by the activation of complement and clotting cascades. In late HCC stages, miR-22-high HCC exhibited heightened innate and adaptive immunity, associated with increased interferon signaling. These impacts were primarily observed in the tumors. At the tumor margin, miR-22 inhibited the Rho GTPase and cell-matrix interaction, revealing its role in reducing matrix remodeling and mobility. In non-tumor areas, miR-22 inhibited inflammation by reducing neutrophil degranulation, platelet activation, Chemokine Receptor binding, and fiber formation. miR-22, Gal-1 silencing, and LLS30 each exhibited anti-HCC effects and targeted common intracellular signaling pathways. Moreover, the anti-HCC effect of miR-22 was dependent on Gal-1 silencing. miR-22-high/Gal-1-low HCC patients had the best survival outcomes. In addition to the above-mentioned key intracellular pathways, miR-22 gene therapy and Gal-1 siRNA treatment of HCC reduced O-linked glycosylation, suggesting the role of the miR-22-Gal-1 axis in modifying glycosylation, which may affect the extracellular functions of Gal-1.

Conclusion: In summary, the miR-22-Gal-1 axis can be an HCC prognostic biomarker, and it has vital roles in regulating metabolism and tumor immunity.

Keywords

Complement; Glycan; Immunity; Liver; Rho GTPase.

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