Adenoviral gene transduction of hepatocyte growth factor elicits inhibitory effects for hepatoma.
Hepatocyte growth factor (HGF) gene therapy may have potential for treating chronic hepatitis (CH) and liver cirrhosis (LC). However, the lack of an HGF gene therapy study on hepatomas that are often associated with CH or LC, together with the stimulatory effects of HGF on many types of cancer, may hamper its application. This study explored the effects of adenoviral HGF gene transduction and their mechanisms on two types of hepatoma cells (hepatoblastoma and hepatocellular carcinoma) in in vitro experiments. Both types of hepatomas were revealed to have higher adenoviral gene transduction efficiencies and more efficient expressions of the HGF transgene, which successfully activated the HGF receptor/c-Met in an autocrine fashion, than those of other types of cancer. Notably, not only HGF, but also adenoviral infection, inhibited DNA synthesis, whereas only HGF but not adenoviral infection exerted a potent apoptotic effect. Moreover, adenoviral HGF gene transduction additively exerted inhibitory effects on cisplatin-treated hepatomas. In conclusion, inhibitory and apoptotic effects of adenoviral HGF gene transduction in hepatomas in contrast to potent mitogenic and antiapoptotic effects of HGF for hepatocytes are not only of biological interest, but also pose clinical benefits for adenoviral HGF gene therapy for CH and LC.
Yuge
Kentaro
K
Department of Gene Therapy and Regenerative Medicine, Gifu University School of Medicine, Japan.
Takahashi
Tomoyuki
T
Nagano
Satoshi
S
Terazaki
Yasuhiro
Y
Murofushi
Yoshiteru
Y
Ushikoshi
Hiroaki
H
Kawai
Takao
T
Khai
Ngin Cin
NC
Nakamura
Toshikazu
T
Fujiwara
Hisayoshi
H
Kosai
Ken-ichiro
K
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013997:Time Factors
C476329:2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt; D013778:Tetrazolium Salts; D017228:Hepatocyte Growth Factor; D004247:DNA; D019859:Proto-Oncogene Proteins c-met; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine; D002945:Cisplatin