Clinical & Experimental Metastasis

, Volume 21, Issue 8, pp 755–764 | Cite as

A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer

  • Yixing Jiang
  • Liwei Wang
  • Weida Gong
  • Daoyan Wei
  • Xiangdong Le
  • James Yao
  • Jaffer Ajani
  • James L. Abbruzzese
  • Suyun Huang
  • Keping Xie


Insulin-like growth factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with transcription factor Sp1 expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Sp1, an important transcription factor for IGF-IR regulation. Knocking-down of Sp1 expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.


gastric cancer IGF-IR lymph node metastasis Sp1 transcription factor 



American Joint Committee on Cancer


constitutive active


confidence interval




insulin-like growth factor receptor I


microvessel density


phosphate-buffered saline


small inhibitory RNA


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  1. 1.
    Parkin, DM, Pisani, P, Ferlay, J. 1999Global cancer statisticsClinical & Experimental Metastasis493364Google Scholar
  2. 2.
    Parkin, DM, Pisani, P, Ferlay, J. 1999Estimates of the worldwide incidence of 25 major cancers in 1990Clinical & Experimental Metastasis8082741Google Scholar
  3. 3.
    Tahara, E. 1993Molecular mechanism of stomach carcinogenesisClinical & Experimental Metastasis11926572Google Scholar
  4. 4.
    Chan, AO, Luk, JM, Jui, WM, Lam, SK. 1999Molecular biology of gastric carcinoma from laboratory to bedsideClinical & Experimental Metastasis14115060Google Scholar
  5. 5.
    Vincent, AM, Feldman, EL. 2002Control of cell survival by IGF signaling pathwaysClinical & Experimental Metastasis121937Google Scholar
  6. 6.
    Moschos, SJ, Mantzoros, CS. 2002The role of the IGF system in cancer: From basic to clinical studies and clinical applicationsClinical & Experimental Metastasis6331732Google Scholar
  7. 7.
    Delafontaine, P. 1995Insulin-like growth factor I and its binding proteins in the cardiovascular systemClinical & Experimental Metastasis3082534Google Scholar
  8. 8.
    Grothey, A, Voigt, W, Schober, C,  et al. 1999The role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis and chemoresistance in solid tumorsClinical & Experimental Metastasis12516673Google Scholar
  9. 9.
    Yu, H, Rohban, T. 2000Role of the insulin-like growth factor family in cancer development and progressionClinical & Experimental Metastasis2000147289Google Scholar
  10. 10.
    Del Giudice, ME, Fantus, IG,  et al. 1998Insulin and related factors in premenopausal breast cancer riskClinical & Experimental Metastasis4711120Google Scholar
  11. 11.
    Bohlke, K, Cramer, DW, Trichopoulos, D, Mantzoros, CS. 1998Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breastClinical & Experimental Metastasis95703Google Scholar
  12. 12.
    Wener, H, Roberts, CT.,Jr 2003The IGFI receptor gene: a molecular target for disrupted transcription factorsClinical & Experimental Metastasis3611320Google Scholar
  13. 13.
    Jiang, Y, Rom, WN, Yie, TA,  et al. 1999Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptorClinical & Experimental Metastasis1860717Google Scholar
  14. 14.
    Adachi, Y, Lee, CT, Coffee, K,  et al. 2002Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell linesClinical & Experimental Metastasis1231191204Google Scholar
  15. 15.
    Reinmuth, N, Fan, F, Liu, W,  et al. 2002Impact of insulin-like growth factor receptor I function on angiogenesis, growth and metastasis of colon cancerClinical & Experimental Metastasis82137799Google Scholar
  16. 16.
    Morrione, A, DeAngelis, T, Baserga, R. 1995Failure of the bovine papillomavirus to transform mouse embryo fibroblasts with a targeted disruption of the insulin-like growth factor I receptor genesClinical & Experimental Metastasis6953003Google Scholar
  17. 17.
    Valentinis, B, Morrione, A, Taylor, SJ, Baserga, R. 1997Insulin-like growth factor I receptor signaling in transformation by src oncogenesClinical & Experimental Metastasis17374454Google Scholar
  18. 18.
    Valentinis, B, Porcu, PL, Quinn, K, Basserga, R. 1994The role of the insulin-like growth factor I receptor in the transformation by simian virus 40 T antigenClinical & Experimental Metastasis982531Google Scholar
  19. 19.
    Sell, C, Rubini, M, Rubin, R,  et al. 1993Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptorClinical & Experimental Metastasis901121721Google Scholar
  20. 20.
    Coppola, D, Ferber, A, Miura, M,  et al. 1994A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptorClinical & Experimental Metastasis14458895Google Scholar
  21. 21.
    Wener, H, Bacj, MA, Stannard, B,  et al. 1992Structural and functional analysis of the insulin-like growth factor I receptor gene promoterClinical & Experimental Metastasis6154558Google Scholar
  22. 22.
    Werner, H, Hernandez-Sanchez, C, Karnieli, E, LeRoith, D. 1995The regulation of IGF-I receptor gene expressionClinical & Experimental Metastasis2798794Google Scholar
  23. 23.
    Wang, L, Wei, D, Huang, S,  et al. 2003Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancerClinical & Experimental Metastasis9637180Google Scholar
  24. 24.
    Yao, J, Wang, L, Wei, D,  et al. 2004Association between expression of Ttranscription factor Sp1 and increased VEGF expression, advanced stage, and poor survival in patients with resected gastric cancerClinical & Experimental Metastasis10410917Google Scholar
  25. 25.
    Abdelrahim, M, Samudio, I, Smith, R,  et al. 2002Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cellsClinical & Experimental Metastasis2772881522Google Scholar
  26. 26.
    Bond, GL, Hu, W, Bond, EE,  et al. 2004A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humansClinical & Experimental Metastasis119591602Google Scholar
  27. 27.
    Wener, H, Re, GG, Drummond, TA,  et al. 1993Increased expression of the insulin-like growth factor I receptor gene, IGFIR, in Wilms’ tumor is correlated with modulation of gene productClinical & Experimental Metastasis90582832Google Scholar
  28. 28.
    Abramovitch, S, Glaser, T, Ouchi, T, Werner, H. 2003BRCA1–Sp1 interactions in transcriptional regulation of the IGF-IR geneClinical & Experimental Metastasis200314954Google Scholar
  29. 29.
    Ohlsson, C, Kley, N, Werner, H, LeRoith, D. 1998p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: Interact between p53 and Sp1Clinical & Experimental Metastasis13911017Google Scholar
  30. 30.
    Webser, NJ, Renik, JL, Reichart, DB,  et al. 1996Repression of the insulin receptor promoter by the tumor suppressor gene product p53: A possible mechanism for receptor overexpression in breast cancerClinical & Experimental Metastasis56278178Google Scholar
  31. 31.
    Chanbert, D, Mohseni-Zadeh, S, Galle, B, Babajko, S. 1999N-myc regulation of type I insulin-like growth factor receptor in a human neuroblastoma cell lineClinical & Experimental Metastasis592898902Google Scholar
  32. 32.
    Shalita-Chesner, M, Katz, J, Shemer, J, Werner, H. 2001Regulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and interferon-gammaClinical & Experimental Metastasis176112Google Scholar
  33. 33.
    Werner, H, Woloschak, M, Adamo, M,  et al. 1989Developmental regulation of the rat insulin-like growth factor I receptor geneClinical & Experimental Metastasis198974515Google Scholar
  34. 34.
    Delafontaine, P. 1995Insulin-like growth factor I and its binding proteins in the cardiovascular systemClinical & Experimental Metastasis3082534Google Scholar
  35. 35.
    Han, RNN, Post, M, Tanswell, AK, Lye, SJ. 2003Insulin-like growth factor I receptor mediated vasilogenesis/angiogenesis in human lung developmentClinical & Experimental Metastasis2815969Google Scholar
  36. 36.
    Strammiello, R, Benini, S, Manara, MC,  et al. 2003Impact of IGF-I/IGF-IR circuit on the angiogenic properties of Ewing’s sarcoma cellsClinical & Experimental Metastasis3567584Google Scholar
  37. 37.
    Warren, RS, Yuan, H, Matli, MR,  et al. 1996Induction of vascular endothelial growth factor by insulin-like growth factor I in colorectal carcinomaClinical & Experimental Metastasis271294838Google Scholar
  38. 38.
    Stoeltzing, O, Liu, W, Reinmuth, N,  et al. 2003Regulation of hypoxia-inducible factor-I alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancerClinical & Experimental Metastasis163100111Google Scholar
  39. 39.
    Courey, AJ, Tjian, R. 1992Mechanisms of transcription factor Sp1Hippel, HYager, TDGill, SC eds. Transcription Regulation.Cold Spring Harbor Laboratory PressCold Spring Harbor, NY74369Google Scholar
  40. 40.
    Bondy, CA, Werner, H, Roberts, CT,Jr, LeRoith, D. 1990Cellular pattern of insulin-like growth factor I (IGF-I) and type I IGF gene expression in early organo-genesis: Comparison with IGF-II gene expressionClinical & Experimental Metastasis4138698Google Scholar
  41. 41.
    Ammendola, R, Mesuraca, M, Russo, T, Cimino, F. 1992Sp1 DNA binding efficiency is highly reduced in nuclear extracts from aged rat tissuesClinical & Experimental Metastasis267179448Google Scholar
  42. 42.
    Xie, K, Wei, D, Shi, Q, Huang, S. 2004Constitutive and inducible expression and regulation of vascular endothelial growth factorClinical & Experimental Metastasis15297324Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Yixing Jiang
    • 1
  • Liwei Wang
    • 1
    • 4
  • Weida Gong
    • 2
  • Daoyan Wei
    • 1
  • Xiangdong Le
    • 1
  • James Yao
    • 1
  • Jaffer Ajani
    • 1
  • James L. Abbruzzese
    • 1
  • Suyun Huang
    • 2
  • Keping Xie
    • 1
    • 3
  1. 1.Department of Gastrointestinal Medical Oncology, Unit 426The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Departments of NeurosurgeryThe University of TexasUSA
  3. 3.Departments of Cancer BiologyThe University of Texas, MD, Anderson Cancer Center, HoustonUSA
  4. 4.Shanghai East Hospital Cancer CenterTongji UniversityShanghaiThe People’s Republic of China

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