Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ad-shIGF-IR:

Adenovirus expressing shRNA targeting IGF-IR

ESCC:

Esophageal squamous cell carcinoma

IGF:

Insulin-like growth factor

IGF-IR:

IGF-I receptor

IR:

Insulin receptor

GI:

Digestive/gastrointestinal

mAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

PI3-K:

Phosphatidylinositide 3-kinase

RNAi:

RNA interference

SC:

Subcutaneous

siRNA:

Small interfering RNA

shIGF-IR:

Short hairpin RNA for IGF-IR

shRNA:

Short hairpin RNA

TKI:

Tyrosine kinase inhibitor

References

  1. Baserga R. Oncogenes and the strategy of growth factors. Cell. 1994;79:927–30.

    Article  CAS  PubMed  Google Scholar 

  2. Adachi Y, Yamamoto H, Imsumran A, Oka T, Oki M, Nosho K, et al. Insulin-like growth factor-I receptor as a candidate for a novel molecular target in the gastrointestinal cancers. Dig Endosc. 2006;18:245–51.

    Article  Google Scholar 

  3. Sara VR, Hall K. Insulin-like growth factors and their binding proteins. Physiol Rev. 1990;70:591–614.

    CAS  PubMed  Google Scholar 

  4. Miller BS, Yee D. Type I insulin-like growth factor receptor as a therapeutic target in cancer. Cancer Res. 2005;65:10123–7.

    Article  CAS  PubMed  Google Scholar 

  5. Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, et al. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J. 1986;5:2503–12.

    CAS  PubMed  Google Scholar 

  6. Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825–31.

    CAS  PubMed  Google Scholar 

  7. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89.

    Article  CAS  PubMed  Google Scholar 

  8. Remacle-Bonnet M, Garrouste F, el Atiq F, Roccabianca M, Marvaldi J, Pommier G. des-(1–3)-IGF-I, an insulin-like growth factor analog used to mimic a potential IGF-II autocrine loop, promotes the differentiation of human colon-carcinoma cells. Int J Cancer. 1992;52:910–7.

    Article  CAS  PubMed  Google Scholar 

  9. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620–5.

    Article  CAS  PubMed  Google Scholar 

  10. Harper J, Burns JL, Foulstone EJ, Pignatelli M, Zaina S, Hassan AB. Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting. Cancer Res. 2006;66:1940–8.

    Article  CAS  PubMed  Google Scholar 

  11. Foulstone E, Prince S, Zaccheo O, Burns JL, Harper J, Jacobs C, et al. Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol. 2005;205:145–53.

    Article  CAS  PubMed  Google Scholar 

  12. Baserga R. The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res. 1995;55:249–52.

    CAS  PubMed  Google Scholar 

  13. Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci USA. 1993;90:11217–21.

    Article  CAS  PubMed  Google Scholar 

  14. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72.

    CAS  PubMed  Google Scholar 

  15. Lahm H, Suardet L, Laurent PL, Fischer JR, Ceyhan A, Givel JC, et al. Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factor I, II and transforming growth factor alpha. Br J Cancer. 1992;65:341–6.

    CAS  PubMed  Google Scholar 

  16. Thompson MA, Cox AJ, Whitehead RH, Jonas HA. Autocrine regulation of human tumor cell proliferation by insulin-like growth factor II: an in vitro model. Endocrinology. 1990;126:3033–42.

    Article  CAS  PubMed  Google Scholar 

  17. Chen SC, Chou CK, Wong FH, Chang CM, Hu CP. Overexpression of epidermal growth factor and insulin-like growth factor-I receptors and autocrine stimulation in human esophageal carcinoma cells. Cancer Res. 1991;51:1898–903.

    CAS  PubMed  Google Scholar 

  18. Imsumran A, Adachi Y, Yamamoto H, Li R, Wang Y, Min Y, et al. Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma. Carcinogenesis. 2007;28:947–56.

    Article  CAS  PubMed  Google Scholar 

  19. Caro JF, Poulos J, Ittoop O, Pories WJ, Flickinger EG, Sinha MK. Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest. 1988;81:976–81.

    Article  CAS  PubMed  Google Scholar 

  20. Kim SO, Park JG, Lee YI. Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: implications of IGF-I receptor gene activation by hepatitis B virus X gene product. Cancer Res. 1996;56:3831–6.

    CAS  PubMed  Google Scholar 

  21. Bergmann U, Funatomi H, Yokoyama M, Beger HG, Korc M. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res. 1995;55:2007–11.

    CAS  PubMed  Google Scholar 

  22. Freier S, Weiss O, Eran M, Flyvbjerg A, Dahan R, Nephesh I, et al. Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon. Gut. 1999;44:704–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ajisaka H, Fushida S, Yonemura Y, Miwa K. Expression of insulin-like growth factor-2, c-MET, matrix metalloproteinase-7 and MUC-1 in primary lesions and lymph node metastatic lesions of gastric cancer. Hepatogastroenterology. 2001;48:1788–92.

    CAS  PubMed  Google Scholar 

  24. Simmons JG, Pucilowska JB, Lund PK. Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors. Am J Physiol. 1999;276:G817–27.

    CAS  PubMed  Google Scholar 

  25. Levitt RJ, Pollak M. Insulin-like growth factor-I antagonizes the antiproliferative effects of cyclooxygenase-2 inhibitors on BxPC-3 pancreatic cancer cells. Cancer Res. 2002;62:7372–6.

    CAS  PubMed  Google Scholar 

  26. Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002;277:39684–95.

    Article  CAS  PubMed  Google Scholar 

  27. Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, et al. Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 2008;68:10238–46.

    Article  CAS  PubMed  Google Scholar 

  28. Schoen RE, Weissfeld JL, Kuller LH, Thaete FL, Evans RW, Hayes RB, et al. Insulin-like growth factor-I and insulin are associated with the presence and advancement of adenomatous polyps. Gastroenterology. 2005;129:464–75.

    PubMed  Google Scholar 

  29. Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res. 2003;63:8912–21.

    CAS  PubMed  Google Scholar 

  30. Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751, 871. Clin Cancer Res. 2005;11:2063–73.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Y, Hailey J, Williams D, Lipari P, Malkowski M, Wang X, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther. 2005;4:1214–21.

    Article  CAS  PubMed  Google Scholar 

  32. Piao W, Wang Y, Adachi Y, Yamamoto H, Li R, Imsumran A, et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther. 2008;7:1483–93.

    Article  CAS  PubMed  Google Scholar 

  33. Huang F, Greer A, Hurlburt W, Han X, Hafezi R, Wittenberg GM, et al. The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res. 2009;69:161–70.

    Article  CAS  PubMed  Google Scholar 

  34. Adachi Y, Lee CT, Coffee K, Yamagata N, Ohm JE, Park KH, et al. Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines. Gastroenterology. 2002;123:1191–204.

    Article  CAS  PubMed  Google Scholar 

  35. Min Y, Adachi Y, Yamamoto H, Ito H, Itoh F, Lee CT, et al. Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer. Cancer Res. 2003;63:6432–41.

    CAS  PubMed  Google Scholar 

  36. Min Y, Adachi Y, Yamamoto H, Imsumran A, Arimura Y, Endo T, et al. Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts. Gut. 2005;54:591–600.

    Article  CAS  PubMed  Google Scholar 

  37. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.

    Article  CAS  PubMed  Google Scholar 

  38. Hannon GJ. RNA interference. Nature. 2002;418:244–51.

    Article  CAS  PubMed  Google Scholar 

  39. Tuschl T. Functional genomics: RNA sets the standard. Nature. 2003;421:220–1.

    Article  CAS  PubMed  Google Scholar 

  40. Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM, et al. The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. J Biol Chem. 2003;278:15991–7.

    Article  CAS  PubMed  Google Scholar 

  41. Rochester MA, Riedemann J, Hellawell GO, Brewster SF, Macaulay VM. Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer. Cancer Gene Ther. 2005;12:90–100.

    Article  CAS  PubMed  Google Scholar 

  42. Dong A, Kong M, Ma Z, Qian J, Cheng H, Xu X. Knockdown of insulin-like growth factor 1 receptor enhances chemosensitivity to cisplatin in human lung adenocarcinoma A549 cells. Acta Biochim Biophys Sin (Shanghai). 2008;40:497–504.

    Article  CAS  Google Scholar 

  43. Lee YJ, Imsumran A, Park MY, Kwon SY, Yoon HI, Lee JH, et al. Adenovirus expressing shRNA to IGF-1R enhances the chemosensitivity of lung cancer cell lines by blocking IGF-1 pathway. Lung Cancer. 2007;55:279–86.

    Article  PubMed  Google Scholar 

  44. Lee CT, Wu S, Gabrilovich D, Chen H, Nadaf-Rahrov S, Ciernik IF, et al. Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines. Cancer Res. 1996;56:3038–41.

    CAS  PubMed  Google Scholar 

  45. Lahm H, Amstad P, Wyniger J, Yilmaz A, Fischer JR, Schreyer M, et al. Blockade of the insulin-like growth-factor-I receptor inhibits growth of human colorectal cancer cells: evidence of a functional IGF-II-mediated autocrine loop. Int J Cancer. 1994;58:452–9.

    Article  CAS  PubMed  Google Scholar 

  46. Kwon J, Stephan S, Mukhopadhyay A, Muders MH, Dutta SK, Lau JS, et al. Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. Cancer Res. 2009;69:1350–7.

    Article  CAS  PubMed  Google Scholar 

  47. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001;93:1852–7.

    Article  CAS  PubMed  Google Scholar 

  48. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.

    Article  CAS  PubMed  Google Scholar 

  49. Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insulin-like growth factor receptor. Cell Mol Life Sci. 2000;57:1050–93.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang H, Pelzer AM, Kiang DT, Yee D. Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. Cancer Res. 2007;67:391–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Yu Wang, Yasushi Adachi, Arisa Imsumran, Hiroyuki Yamamoto, Wenhua Piao, Hua Li, Masanori Ii, Yoshiaki Arimura, Kohzoh Imai & Yasuhisa Shinomura

  2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute Seoul National University College of Medicine, Seoul, Korea

    Mi Young Park, Dalrae Kim & Choon-Taek Lee

  3. Departments of Medicine and Cell Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, 37232-6838, USA

    David P. Carbone

Authors
  1. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasushi Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arisa Imsumran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenhua Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masanori Ii
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshiaki Arimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mi Young Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dalrae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Choon-Taek Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David P. Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kohzoh Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yasuhisa Shinomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasushi Adachi.

Additional information

Y. Wang and Y. Adachi contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Adachi, Y., Imsumran, A. et al. Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers. J Gastroenterol 45, 159–170 (2010). https://doi.org/10.1007/s00535-009-0151-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-009-0151-6

Keywords

Search

Navigation