Document Detail


Apoptotic pathway induced by transduction of RUNX3 in the human gastric carcinoma cell line MKN-1.
MedLine Citation:
PMID:  17956589     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The human runt-related transcription factor 3 gene (RUNX3) is considered to be a candidate tumor suppressor gene in gastric carcinoma. However, the role of RUNX3 in the regulation of cell proliferation remains unclear. In the present study, we constructed an adenoviral vector encoding human RUNX3 cDNA under the control of a Tet-responsive promoter (Ad-Tet-FLAG-RUNX3), which regulates the expression of RUNX3 in the presence or absence of doxycycline. A recombinant adenoviral expression vector encoding LacZ (Ad-Tet-LacZ) was used as a negative control. The effect of the transduction of RUNX3 on cell growth was examined using the Tet-On system in a human gastric carcinoma cell line, MKN-1. Exogenous RUNX3 expression was induced successfully by Ad-Tet-FLAG-RUNX3, but not Ad-Tet-LacZ, in the presence of doxycycline in the MKN-1 cells. At 72 h after infection, the proliferative activity in RUNX3-expressing cells was 55% or less of that of the control cells. Flow cytometry revealed that the sub-G(1) peak was increased in cells expressing RUNX3 (34.11%), indicating that the inhibition of cell growth was due to apoptosis, which was confirmed based on Hoechst 33258 staining, the release of cytochrome c from mitochondria into the cytosol, and detection of cleaved caspase-3 by western blotting in MKN-1 cells. Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. Pathway analyses to generate functional networks of the genes suggested that promotion of the formation of the death-inducing signaling complex and activation of the mitochondria-mediated pathway were associated with RUNX3-induced apoptosis. In conclusion, our findings suggest that exogenous RUNX3 expression suppressed cell proliferation by inducing apoptosis via the death-receptor mitochondria-mediated pathway in MKN-1 cells.
Authors:
Yumi Nagahama; Mika Ishimaru; Mitsuhiko Osaki; Toshiaki Inoue; Akihiro Maeda; Chisato Nakada; Masatsugu Moriyama; Kenzo Sato; Mitsuo Oshimura; Hisao Ito
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-22
Journal Detail:
Title:  Cancer science     Volume:  99     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2007-12-18     Completed Date:  2008-02-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  23-30     Citation Subset:  IM    
Affiliation:
Division of Organ Pathology, Department of Microbiology and Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8503, Japan.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Apoptosis / genetics*
Cell Growth Processes / genetics
Cell Line, Tumor
Core Binding Factor Alpha 3 Subunit / biosynthesis,  genetics*
DNA, Complementary / genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Vectors / genetics
Humans
Oligonucleotide Array Sequence Analysis
Stomach Neoplasms / genetics*,  pathology
Tetracycline / pharmacology
Transduction, Genetic
Chemical
Reg. No./Substance:
0/Core Binding Factor Alpha 3 Subunit; 0/DNA, Complementary; 0/Runx3 protein, human; 60-54-8/Tetracycline

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