Document Detail

miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines.
MedLine Citation:
PMID:  21055388     Owner:  NLM     Status:  MEDLINE    
Previous work by us and others reported decreased expression of miR-199a-3p in hepatocellular carcinoma (HCC) tissues compared to adjacent benign tissue. We report here a significant reduction of miR-199a-3p expression in 7 HCC cell lines. To determine if miR-199a-3p has a tumor suppressive role, pre-miR-199a-3p oligonucleotides were transfected into the HCC cell lines. Pre-miR-199a-3p oligonucleotide reduced cell proliferation by approximately 60% compared to control oligonucleotide in only two cell lines (SNU449 and SNU423); the proliferation of the other 5 treated cell lines was similar to control oligonucleotide. A pre-miR-199a-3p oligonucleotide formulated with chemical modifications to enhance stability while preserving processing, reduced cell proliferation in SNU449 and SNU423 to the same extent as the commercially available pre-miR-199a-3p oligonucleotide. Furthermore, only the duplex miR-199a-3p oligonucleotide, and not the guide strand alone, was effective at reducing cell viability. Since a CD44 variant was essential for c-Met signaling [V. Orian-Rousseau, L. Chen, J.P. Sleeman, P. Herrlich, H. Ponta, CD44 is required for two consecutive steps in HGF/c-Met signaling, Genes Dev. 16 (2002) 3074-3086] and c-Met is a known miR-199a-3p target, we hypothesized that miR-199a-3p may also target CD44. Immunoblotting confirmed that only the two HCC lines that were sensitive to the effects of pre-miR-199a-3p were CD44+. Direct targeting of CD44 by miR-199a-3p was confirmed using luciferase reporter assays and immunoblotting. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin; both effects were enhanced when hyaluronic acid (HA) was added to the cell cultures. An inverse correlation between the expression of miR-199a-3p and CD44 protein was noted in primary HCC specimens. The ability of miR-199a-3p to selectively kill CD44+ HCC may be a useful targeted therapy for CD44+ HCC.
Jon C Henry; Jong-Kook Park; Jinmai Jiang; Ji Hye Kim; David M Nagorney; Lewis R Roberts; Soma Banerjee; Thomas D Schmittgen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-11-03
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  403     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-01-13     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  120-5     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
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MeSH Terms
Antibiotics, Antineoplastic / pharmacology
Antigens, CD44 / genetics*
Carcinoma, Hepatocellular / genetics,  metabolism,  pathology*
Cell Line, Tumor
Cell Proliferation
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Genes, Tumor Suppressor*
Liver Neoplasms / genetics,  metabolism,  pathology*
MicroRNAs / genetics*
Neoplasm Invasiveness
Grant Support
R33 CA114304/CA/NCI NIH HHS; R33 CA114304-04/CA/NCI NIH HHS; R33CA114304/CA/NCI NIH HHS
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antigens, CD44; 0/MicroRNAs; 0/mirn199 microRNA, human; 80168379AG/Doxorubicin

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