title: Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, W-16 Chuo-ku, Sapporo 060-8543, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Arisa
authors.initials: A
authors.lastname: Imsumran
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Wenhua
authors.initials: W
authors.lastname: Piao
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Masanori
authors.initials: M
authors.lastname: Ii
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Arimura
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Park
authors.forename: Dalrae
authors.initials: D
authors.lastname: Kim
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D007328:Insulin; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin