Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers
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Background and aims
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.
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.
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.
shIGF-IR may have therapeutic utility in human digestive/gastrointestinal cancers, both alone and in combination with chemotherapy.
KeywordsCombination therapy Digestive/gastrointestinal cancers Insulin like growth factor -I receptor (IGF-IR) RNAi Short hairpin RNA
Adenovirus expressing shRNA targeting IGF-IR
Esophageal squamous cell carcinoma
Insulin-like growth factor
Mitogen-activated protein kinase
Extracellular signal-regulated kinase
Small interfering RNA
Short hairpin RNA for IGF-IR
Short hairpin RNA
Tyrosine kinase inhibitor
This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology and from the Ministry of Health, Labour and Welfare, Japan. This work was also supported in part by Pancreatic Research Foundation of Japan and by National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0320120-2).
Conflict of interest statement
No conflicts of interest exist.
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