miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by Inducing Apoptosis of CD24+ Progenitor Cells

Abstract

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 αv. 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 expansion of S100A4+ cancer-associated stromal cells and associated liver fibrosis.

Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population

“…In the liver, OPN has been shown to modulate regeneration, inflammation and fibrosis and more recently, to induce dedifferentiation of hepatocytes (37,38). Our group has also shown that OPN is necessary for the survival of CD24 + liver progenitor cells (39). Both dedifferentiation of hepatocytes and accumulation of CD24 + cells have been proposed as early events in HCC tumor initiation (40,41).…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Both plastic stents and self-expandable metallic stents can be utilized, but self-expandable metallic stents seem to offer several advantages, including higher patency duration than plastic stents 264 . 267,268 and fusion genes 68,74,79,269 . Targeted anti-fibrotic therapy is also under investigation 183 .…”

Stress-activatedmiR-21/miR-21*in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption

“…For example, increased miR-21 expression might play an important role in liver fibrosis, consistent with previous studies examining the role of miR-21 in kidney, heart and lung fibrosis 15–20. In cholangiocarcinoma and HCC, miR-21 is upregulated, thereby inhibiting the expression of crucial tumour suppressors and favouring hepatic cells survival 19 21–24 . miR-21 also regulates early phases of liver regeneration following partial hepatectomy 25 26.…”