title: 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 the expansion of S100A4(+) cancer-associated stromal cells and associated liver fibrosis.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cermelli
authors.affiliation: Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kyle
authors.initials: K
authors.lastname: Muir
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kwang Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Ruhai
authors.initials: R
authors.lastname: Zou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Regulus Therapeutics, Inc, San Diego, California.
authors.forename: Sonya
authors.initials: S
authors.lastname: Zabludoff
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Beretta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051927:CD24 Antigen / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D039564:Integrin alphaV / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D053495:Osteopontin / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics
chemical_list: D051927:CD24 Antigen; D039564:Integrin alphaV; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; C506896:Spp1 protein, mouse; D053495:Osteopontin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse