miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by
Inducing Apoptosis of CD24+ Progenitor Cells
#MMPMID25769721
Zhang J
; Jiao J
; Cermelli S
; Muir K
; Jung KH
; Zou R
; Rashid A
; Gagea M
; Zabludoff S
; Kalluri R
; Beretta L
Cancer Res
2015[May]; 75
(9
): 1859-67
PMID25769721
show ga
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 ?v. 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.
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