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

Yu Wang, Yasushi Adachi, Arisa Imsumran, Hiroyuki Yamamoto, Wenhua Piao, Hua Li, Masanori Ii, Yoshiaki Arimura, Mi Young Park, Dalrae Kim, Choon Taek Lee, David P. Carbone, Kohzoh Imai, Yasuhisa Shinomura

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Abstract

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.

Original languageEnglish
Pages (from-to)159-170
Number of pages12
JournalJournal of Gastroenterology
Volume45
Issue number2
DOIs
StatePublished - 1 Feb 2010

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IGF Type 1 Receptor
Gastrointestinal Neoplasms
Small Interfering RNA
Somatomedins
Insulin Receptor
Adenoviridae
Drug Therapy
Insulin
Apoptosis
Somatomedin Receptors
RNA Interference
Combination Drug Therapy
Heterografts
Nude Mice
Hepatocellular Carcinoma
Signal Transduction
Neoplasms
Stomach
Adenocarcinoma
Cell Line

Keywords

  • Combination therapy
  • Digestive/gastrointestinal cancers
  • Insulin like growth factor -I receptor (IGF-IR)
  • RNAi
  • Short hairpin RNA

Cite this

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. / Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers. In: Journal of Gastroenterology. 2010 ; Vol. 45, No. 2. pp. 159-170.
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title = "Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers",
abstract = "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.",
keywords = "Combination therapy, Digestive/gastrointestinal cancers, Insulin like growth factor -I receptor (IGF-IR), RNAi, Short hairpin RNA",
author = "Yu Wang and Yasushi Adachi and Arisa Imsumran and Hiroyuki Yamamoto and Wenhua Piao and Hua Li and Masanori Ii and Yoshiaki Arimura and Park, {Mi Young} and Dalrae Kim and Lee, {Choon Taek} and Carbone, {David P.} and Kohzoh Imai and Yasuhisa Shinomura",
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Wang, Y, Adachi, Y, Imsumran, A, Yamamoto, H, Piao, W, Li, H, Ii, M, Arimura, Y, Park, MY, Kim, D, Lee, CT, Carbone, DP, Imai, K & Shinomura, Y 2010, 'Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers', Journal of Gastroenterology, vol. 45, no. 2, pp. 159-170. https://doi.org/10.1007/s00535-009-0151-6

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

In: Journal of Gastroenterology, Vol. 45, No. 2, 01.02.2010, p. 159-170.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers

AU - Wang, Yu

AU - Adachi, Yasushi

AU - Imsumran, Arisa

AU - Yamamoto, Hiroyuki

AU - Piao, Wenhua

AU - Li, Hua

AU - Ii, Masanori

AU - Arimura, Yoshiaki

AU - Park, Mi Young

AU - Kim, Dalrae

AU - Lee, Choon Taek

AU - Carbone, David P.

AU - Imai, Kohzoh

AU - Shinomura, Yasuhisa

PY - 2010/2/1

Y1 - 2010/2/1

N2 - 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.

AB - 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.

KW - Combination therapy

KW - Digestive/gastrointestinal cancers

KW - Insulin like growth factor -I receptor (IGF-IR)

KW - RNAi

KW - Short hairpin RNA

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DO - 10.1007/s00535-009-0151-6

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SN - 0944-1174

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