Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice.
Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SRalpha promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes.
Kanbe
Takamasa
T
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
Murai
Rie
R
Mukoyama
Tomoyuki
T
Murawaki
Yoshiyuki
Y
Hashiguchi
Ko-ichi
K
Yoshida
Yoko
Y
Tsuchiya
Hiroyuki
H
Kurimasa
Akihiro
A
Harada
Ken-ichi
K
Yashima
Kazuo
K
Nishimuki
Eiji
E
Shabana
Noriko
N
Kishimoto
Yukihiro
Y
Kojyo
Haruhiko
H
Miura
Kunihiko
K
Murawaki
Yoshikazu
Y
Kawasaki
Hironaka
H
Shiota
Goshi
G
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D017228:Hepatocyte Growth Factor; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3