Gene therapy using ets-1 transcription factor decoy for peritoneal dissemination of gastric cancer.
The ets-1 transcription factor plays an important role in cell proliferation, differentiation, apoptosis and tissue remodeling. Aberrant ets-1 expression correlates with aggressive tumor behavior and poorer prognosis in patients with various malignancies. This study evaluated the efficacy of double-stranded decoy oligonucleotides targeting ets-1-binding cis elements for the suppression of ets-1 in treatment of a peritoneal dissemination model of gastric cancer. In vitro, MTT assay was performed to evaluate the effect of the ets-1 decoy on cell growth. Electrophoretic mobility shift assay (EMSA) was performed to determine ets-1 activity. In vivo, the effect of the ets-1 decoy was investigated in the peritoneal dissemination nude mice model. Disseminated nodules were analyzed immunohistochemically. Ets-1 decoy, but not scrambled decoy, significantly inhibited cell growth in 2 gastric cancer cell lines, which showed overexpression of ets-1 protein by inhibiting the binding activity of ets-1. In the peritoneal dissemination model, the ets-1 decoy significantly suppressed the disseminated nodules, and tended to prolong the survival rate. PCNA index, microvessel density and VEGF expression were also reduced in peritoneal tumors treated with ets-1 decoy. Intraperitoneal injection of ets-1 decoy inhibited peritoneal dissemination of gastric cancer in a nude mice model. The results indicate that the decoy strategy for ets-1 offers a promising therapy for patients with incurable peritoneal dissemination of gastric cancer, most of which show overexpression of ets-1 protein.
Taniguchi
Hirokazu
H
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Fujiwara
Yoshiyuki
Y
Doki
Yuichiro
Y
Sugita
Yurika
Y
Sohma
Itsuro
I
Miyata
Hiroshi
H
Takiguchi
Shuji
S
Yasuda
Takushi
T
Tomita
Naruya
N
Morishita
Ryuichi
R
Monden
Morito
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D009841:Oligonucleotides; D050784:Proto-Oncogene Protein c-ets-1; D049452:Green Fluorescent Proteins