miR-21 inhibition reduces liver fibrosis and prevents tumor development by inducing apoptosis of CD24⁺ progenitor cells

miR-21 is upregulated in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, where it is associated with poor prognosis. Here, we offer preclinical evidence that miR-21 offers a therapeutic and chemopreventive target in these liver cancers. In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development. These effects were accompanied with a decrease in liver fibrosis and a concomitant reduction of CD24⁺ liver progenitor cells and S100A4⁺ cancer-associated stromal cells. Notch2 inhibition also occurred in tumors following anti-miR-21 treatment. We further showed that miR-21 is necessary for the survival of CD24⁺ progenitor cells, a cellular phenotype mediated by Notch2, osteopontin, and integrin av. Our results identify miR-21 as a key regulator of tumor-initiating cell survival, malignant development, and growth in liver cancer, highlighting the role of CD24⁺ cells in the expansion of S100A4⁺ cancer-associated stromal cells and associated liver fibrosis.