Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers.
OBJECTIVE
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling plays important parts in both the tumorigenicity and progression of digestive/gastrointestinal malignancies. In this study, we sought to test the effectiveness of a practical approach to blocking IGF-IR signaling using RNA interference delivered by recombinant adenoviruses.


METHODS
We constructed a recombinant adenovirus expressing short hairpin RNA targeting IGF-IR (shIGF-IR) and assessed its effect on signal transduction, proliferation, and survival in digestive/gastrointestinal cancer cell lines representing colorectal, gastric, and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. We analyzed the effects of shIGF-IR alone and with chemotherapy in vitro and in nude mouse xenografts, as well as on insulin signaling and hybrid receptor formation between IGF-IR and insulin receptor.


RESULTS
shIGF-IR blocked expression and autophosphorylation of IGF-IR and downstream signaling by the IGFs, but not by insulin. shIGF-IR suppressed proliferation and carcinogenicity in vitro and up-regulated apoptosis in a dose-dependent fashion. shIGF-IR augmented the effects of chemotherapy on in vitro growth and apoptosis induction. Moreover, the combination of shIGF-IR and chemotherapy was highly effective against tumors in mice. shIGF-IR reduced hybrid receptor formation without effect on expression of insulin receptor.


CONCLUSIONS
shIGF-IR may have therapeutic utility in human digestive/gastrointestinal cancers, both alone and in combination with chemotherapy.
Wang
Yu
Y
First Department of Internal Medicine, Sapporo Medical University, W-16 Chuo-ku, Sapporo 060-8543, Japan.
Adachi
Yasushi
Y
Imsumran
Arisa
A
Yamamoto
Hiroyuki
H
Piao
Wenhua
W
Li
Hua
H
Ii
Masanori
M
Arimura
Yoshiaki
Y
Park
Mi Young
MY
Kim
Dalrae
D
Lee
Choon-Taek
CT
Carbone
David P
DP
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000503:physiopathology / Q000628:therapy*; D018390:Gene Targeting / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin