MiR-22/GLUT1 Axis Induces Metabolic Reprogramming and Sorafenib Resistance in Hepatocellular Carcinoma
The approval of immunotherapy has revolutionized the management of hepatocellular carcinoma (HCC) patients. However, sorafenib remains a first-line therapeutic option for advanced patients and, in particular, for patients not eligible for immune checkpoint inhibitors, but its efficacy is limited by the onset of acquired resistance, highlighting the urgent need for predictive biomarkers. This study investigates the role of miR-22 in metabolic reprogramming and its potential as a biomarker in HCC. The analysis of miR-22 expression was performed in HCC patients and preclinical models by qPCR. Functional analyses in HCC cells evaluated GLUT1 as a direct miR-22 target. Cellular and metabolic assays evaluated the miR-22/GLUT1 axis's role in metabolic changes, tumor aggressiveness, and sorafenib response. Circulating miR-22 was analyzed in sorafenib-treated HCC patients and rats. MiR-22 was downregulated in HCCs and associated with aggressive tumor features. Functionally, miR-22 modulated the HIF1A pathway, enhanced survival in stressful conditions, promoted a glycolytic shift, and enhanced cancer cell plasticity and sorafenib resistance via GLUT1 targeting. In addition, high serum miR-22 levels were associated with sorafenib resistance in HCC patients and rats. GLUT1 inhibition sensitized low miR-22-expressing HCC cells to sorafenib in preclinical models. These findings suggest that circulating miR-22 deserves attention as a predictive biomarker of sorafenib response. GLUT1 inhibition may represent a therapeutic strategy to combine with sorafenib, particularly in patients exhibiting high circulating miR-22 levels.
Authors
- Marianna Moro (ORCID: https://orcid.org/0009-0006-5518-7214)
- Romana Fato (ORCID: https://orcid.org/0000-0002-8945-6826)
- Maurizio Baldassarre (ORCID: https://orcid.org/0000-0001-7865-394X)
- Marco Domenicali (ORCID: https://orcid.org/0000-0002-5065-7073)
- Catia Giovannini (ORCID: https://orcid.org/0000-0003-1904-1577)
- Matteo Cescon (ORCID: https://orcid.org/0000-0003-1715-3794)
- Fabio Piscaglia (ORCID: https://orcid.org/0000-0001-8264-1845)
- Elisa Monti (ORCID: https://orcid.org/0009-0005-0679-6075)
- Claudio Stefanelli (ORCID: https://orcid.org/0000-0001-5864-2178)
- Francesco Vasuri (ORCID: https://orcid.org/0000-0002-1145-6025)
- Valeria Righi (ORCID: https://orcid.org/0000-0003-2394-8462)
- Camelia Alexandra Coadǎ (ORCID: https://orcid.org/0000-0001-8362-6639)
- Giuseppe Galvani (ORCID: https://orcid.org/0000-0002-4533-9134)
- Ilaria Leoni
- Francesca Fornari (ORCID: https://orcid.org/0000-0002-4302-4411)
- Alessandro Perrone (ORCID: https://orcid.org/0000-0002-0905-2195)
- Matteo Ravaioli (ORCID: https://orcid.org/0000-0001-5862-6151)
- Sara Marinelli (ORCID: https://orcid.org/0000-0001-5393-4796)
- Ambra A. Grolla (ORCID: https://orcid.org/0000-0003-0233-0700)
- Milena Pariali
- Clara Vianello
- Laura Gramantieri (ORCID: https://orcid.org/0000-0002-5187-9559)
- Massimo Negrini (ORCID: https://orcid.org/0000-0002-0007-1920)
- Gloria Ravegnini (ORCID: https://orcid.org/0000-0002-7774-402X)
- Luca Pincigher (ORCID: https://orcid.org/0009-0002-9806-2789)
- Francesca Valenti (ORCID: https://orcid.org/0000-0002-7266-7352)
- Christian Bergamini (ORCID: https://orcid.org/0000-0003-4387-5117)
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Ferrara (IT)
- Ospedale "Santa Maria delle Croci" di Ravenna (IT)
- Medica (Italy) (IT)
- Azienda USL di Bologna (IT)
- University of Bologna (IT)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-04-17
- DOI
- https://doi.org/10.3390/ijms26083808
- Citations
- 2
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.87