ADARp110 promotes hepatocellular carcinoma progression via stabilization of CD24 mRNA.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39808660.
- Also identified by DOI 10.1073/pnas.2409724122 and PMC identifier 11761664.
- Licence recorded as CC BY-NC-ND.
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Abstract
ADAR is highly expressed and correlated with poor prognosis in hepatocellular carcinoma (HCC), yet the role of its constitutive isoform ADARp110 in tumorigenesis remains elusive. We investigated the role of ADARp110 in HCC and underlying mechanisms using clinical samples, a hepatocyte-specific <i>Adarp110</i> knock-in mouse model, and engineered cell lines. ADARp110 is overexpressed and associated with poor survival in both human and mouse HCC. It creates an immunosuppressive microenvironment by inhibiting total immune cells, particularly cytotoxic GZMB<sup>+</sup>CD8<sup>+</sup> T cells infiltration, while augmenting Treg cells, MDSCs, and exhausted CD8<sup>+</sup> T cells ratios. Mechanistically, ADARp110 interacts with SNRPD3 and RNPS1 to stabilize CD24 mRNA by inhibiting STAU1-mediated mRNA decay. CD24 protects HCC cells from two indispensable mechanisms: macrophage phagocytosis and oxidative stress. Genetic knockdown or monoclonal antibody treatment of CD24 inhibits ADARp110-overexpressing tumor growth. Our findings unveil different mechanisms for ADARp110 modulation of tumor immune microenvironment and identify CD24 as a promising therapeutic target for HCCs.
Medical subject headings
- Carcinoma, Hepatocellular
- Liver Neoplasms
- CD24 Antigen
- RNA-Binding Proteins
- RNA, Messenger
- RNA Stability