Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers

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 usin...

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Published in:	Journal of gastroenterology Vol. 45; no. 2; pp. 159 - 170
Main Authors:	Wang, Yu, Adachi, Yasushi, Imsumran, Arisa, Yamamoto, Hiroyuki, Piao, Wenhua, Li, Hua, Ii, Masanori, Arimura, Yoshiaki, Park, Mi Young, Kim, Dalrae, Lee, Choon-Taek, Carbone, David P, Imai, Kohzoh, Shinomura, Yasuhisa
Format:	Journal Article
Language:	English
Published:	Japan Japan : Springer Japan 01-02-2010 Springer Japan Springer Springer Nature B.V
Subjects:	Abdominal Surgery Adenoviridae - genetics Adenovirus Adenoviruses Analysis Animals Antineoplastic Agents - pharmacology Apoptosis Cancer Cell Line, Tumor Cell Proliferation Cellular signal transduction Chemotherapy Colorectal Surgery Combined Modality Therapy Dose-Response Relationship, Drug Esophageal cancer Female Gastroenterology Gastrointestinal Neoplasms - physiopathology Gastrointestinal Neoplasms - therapy Gene Targeting - methods Genetic Vectors Health aspects Hepatology Humans Insulin - metabolism Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Nude Original Article—Alimentary Tract Pancreatic cancer Receptor, IGF Type 1 - antagonists & inhibitors Receptor, IGF Type 1 - metabolism Receptor, Insulin - metabolism RNA RNA, Small Interfering - administration & dosage Signal Transduction Squamous cell carcinoma Surgical Oncology Xenograft Model Antitumor Assays RNAi Insulin like growth factor -I receptor (IGF-IR) Digestive/gastrointestinal cancers Combination therapy Short hairpin RNA
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Summary:	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. 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.
Bibliography:	http://dx.doi.org/10.1007/s00535-009-0151-6 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0944-1174 1435-5922
DOI:	10.1007/s00535-009-0151-6