Format

Send to

Choose Destination
Cancer Res. 2015 May 1;75(9):1859-67. doi: 10.1158/0008-5472.CAN-14-1254. Epub 2015 Mar 13.

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

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. State Key Laboratory of Oncology in Southern China, Department of Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Regulus Therapeutics, Inc, San Diego, California.
7
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. lberetta@mdanderson.org.

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 the expansion of S100A4(+) cancer-associated stromal cells and associated liver fibrosis.

PMID:
25769721
PMCID:
PMC4603420
DOI:
10.1158/0008-5472.CAN-14-1254
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center