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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

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Abstract

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.

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Abbreviations

AJCC:

American Joint Committee on Cancer

CA:

constitutive active

CI:

confidence interval

DN:

dominant-negative

IGF-IR:

insulin-like growth factor receptor I

MVD:

microvessel density

PBS:

phosphate-buffered saline

siRNA:

small inhibitory RNA

References

  1. DM Parkin P Pisani J. Ferlay (1999) ArticleTitleGlobal cancer statistics Clinical & Experimental Metastasis 49 33–64

    Google Scholar 

  2. DM Parkin P Pisani J. Ferlay (1999) ArticleTitleEstimates of the worldwide incidence of 25 major cancers in 1990 Clinical & Experimental Metastasis 80 827–41

    Google Scholar 

  3. E. Tahara (1993) ArticleTitleMolecular mechanism of stomach carcinogenesis Clinical & Experimental Metastasis 119 265–72

    Google Scholar 

  4. AO Chan JM Luk WM Jui SK. Lam (1999) ArticleTitleMolecular biology of gastric carcinoma from laboratory to bedside Clinical & Experimental Metastasis 14 1150–60

    Google Scholar 

  5. AM Vincent EL. Feldman (2002) ArticleTitleControl of cell survival by IGF signaling pathways Clinical & Experimental Metastasis 12 193–7

    Google Scholar 

  6. SJ Moschos CS. Mantzoros (2002) ArticleTitleThe role of the IGF system in cancer: From basic to clinical studies and clinical applications Clinical & Experimental Metastasis 63 317–32

    Google Scholar 

  7. P. Delafontaine (1995) ArticleTitleInsulin-like growth factor I and its binding proteins in the cardiovascular system Clinical & Experimental Metastasis 30 825–34

    Google Scholar 

  8. A Grothey W Voigt C Schober et al. (1999) ArticleTitleThe role of insulin-like growth factor I and its receptor in cell growth, transformation, apoptosis and chemoresistance in solid tumors Clinical & Experimental Metastasis 125 166–73

    Google Scholar 

  9. H Yu T. Rohban (2000) ArticleTitleRole of the insulin-like growth factor family in cancer development and progression Clinical & Experimental Metastasis 2000 IssueID92 1472–89

    Google Scholar 

  10. ME Del Giudice IG Fantus et al. (1998) ArticleTitleInsulin and related factors in premenopausal breast cancer risk Clinical & Experimental Metastasis 47 111–20

    Google Scholar 

  11. K Bohlke DW Cramer D Trichopoulos CS. Mantzoros (1998) ArticleTitleInsulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast Clinical & Experimental Metastasis 9 570–3

    Google Scholar 

  12. H Wener CT. Roberts SuffixJr (2003) ArticleTitleThe IGFI receptor gene: a molecular target for disrupted transcription factors Clinical & Experimental Metastasis 36 113–20

    Google Scholar 

  13. Y Jiang WN Rom TA Yie et al. (1999) ArticleTitleInduction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor Clinical & Experimental Metastasis 18 6071–7

    Google Scholar 

  14. Y Adachi CT Lee K Coffee et al. (2002) ArticleTitleEffects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines Clinical & Experimental Metastasis 123 1191–204

    Google Scholar 

  15. N Reinmuth F Fan W Liu et al. (2002) ArticleTitleImpact of insulin-like growth factor receptor I function on angiogenesis, growth and metastasis of colon cancer Clinical & Experimental Metastasis 82 1377–99

    Google Scholar 

  16. A Morrione T DeAngelis R. Baserga (1995) ArticleTitleFailure of the bovine papillomavirus to transform mouse embryo fibroblasts with a targeted disruption of the insulin-like growth factor I receptor genes Clinical & Experimental Metastasis 69 5300–3

    Google Scholar 

  17. B Valentinis A Morrione SJ Taylor R. Baserga (1997) ArticleTitleInsulin-like growth factor I receptor signaling in transformation by src oncogenes Clinical & Experimental Metastasis 17 3744–54

    Google Scholar 

  18. B Valentinis PL Porcu K Quinn R. Basserga (1994) ArticleTitleThe role of the insulin-like growth factor I receptor in the transformation by simian virus 40 T antigen Clinical & Experimental Metastasis 9 825–31

    Google Scholar 

  19. C Sell M Rubini R Rubin et al. (1993) ArticleTitleSimian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor Clinical & Experimental Metastasis 90 11217–21

    Google Scholar 

  20. D Coppola A Ferber M Miura et al. (1994) ArticleTitleA functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor Clinical & Experimental Metastasis 14 4588–95

    Google Scholar 

  21. H Wener MA Bacj B Stannard et al. (1992) ArticleTitleStructural and functional analysis of the insulin-like growth factor I receptor gene promoter Clinical & Experimental Metastasis 6 1545–58

    Google Scholar 

  22. H Werner C Hernandez-Sanchez E Karnieli D. LeRoith (1995) ArticleTitleThe regulation of IGF-I receptor gene expression Clinical & Experimental Metastasis 27 987–94

    Google Scholar 

  23. L Wang D Wei S Huang et al. (2003) ArticleTitleTranscription factor Sp1 expression is a significant predictor of survival in human gastric cancer Clinical & Experimental Metastasis 9 6371–80

    Google Scholar 

  24. J Yao L Wang D Wei et al. (2004) ArticleTitleAssociation between expression of Ttranscription factor Sp1 and increased VEGF expression, advanced stage, and poor survival in patients with resected gastric cancer Clinical & Experimental Metastasis 10 4109–17

    Google Scholar 

  25. M Abdelrahim I Samudio R Smith et al. (2002) ArticleTitleSmall inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells Clinical & Experimental Metastasis 277 28815–22

    Google Scholar 

  26. GL Bond W Hu EE Bond et al. (2004) ArticleTitleA single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans Clinical & Experimental Metastasis 119 591–602

    Google Scholar 

  27. H Wener GG Re TA Drummond et al. (1993) ArticleTitleIncreased expression of the insulin-like growth factor I receptor gene, IGFIR, in Wilms’ tumor is correlated with modulation of gene product Clinical & Experimental Metastasis 90 5828–32

    Google Scholar 

  28. S Abramovitch T Glaser T Ouchi H. Werner (2003) ArticleTitleBRCA1–Sp1 interactions in transcriptional regulation of the IGF-IR gene Clinical & Experimental Metastasis 2003 IssueID541 149–54

    Google Scholar 

  29. C Ohlsson N Kley H Werner D. LeRoith (1998) ArticleTitlep53 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 Sp1 Clinical & Experimental Metastasis 139 1101–7

    Google Scholar 

  30. NJ Webser JL Renik DB Reichart et al. (1996) ArticleTitleRepression of the insulin receptor promoter by the tumor suppressor gene product p53: A possible mechanism for receptor overexpression in breast cancer Clinical & Experimental Metastasis 56 2781–78

    Google Scholar 

  31. D Chanbert S Mohseni-Zadeh B Galle Particlede S. Babajko (1999) ArticleTitleN-myc regulation of type I insulin-like growth factor receptor in a human neuroblastoma cell line Clinical & Experimental Metastasis 59 2898–902

    Google Scholar 

  32. M Shalita-Chesner J Katz J Shemer H. Werner (2001) ArticleTitleRegulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and interferon-gamma Clinical & Experimental Metastasis 176 1–12

    Google Scholar 

  33. H Werner M Woloschak M Adamo et al. (1989) ArticleTitleDevelopmental regulation of the rat insulin-like growth factor I receptor gene Clinical & Experimental Metastasis 1989 IssueID86 7451–5

    Google Scholar 

  34. P. Delafontaine (1995) ArticleTitleInsulin-like growth factor I and its binding proteins in the cardiovascular system Clinical & Experimental Metastasis 30 825–34

    Google Scholar 

  35. RNN Han M Post AK Tanswell SJ. Lye (2003) ArticleTitleInsulin-like growth factor I receptor mediated vasilogenesis/angiogenesis in human lung development Clinical & Experimental Metastasis 28 159–69

    Google Scholar 

  36. R Strammiello S Benini MC Manara et al. (2003) ArticleTitleImpact of IGF-I/IGF-IR circuit on the angiogenic properties of Ewing’s sarcoma cells Clinical & Experimental Metastasis 35 675–84

    Google Scholar 

  37. RS Warren H Yuan MR Matli et al. (1996) ArticleTitleInduction of vascular endothelial growth factor by insulin-like growth factor I in colorectal carcinoma Clinical & Experimental Metastasis 271 29483–8

    Google Scholar 

  38. O Stoeltzing W Liu N Reinmuth et al. (2003) ArticleTitleRegulation 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 cancer Clinical & Experimental Metastasis 163 1001–11

    Google Scholar 

  39. AJ Courey R. Tjian (1992) Mechanisms of transcription factor Sp1 H Hippel Particlevon TD Yager SC Gill (Eds) Transcription Regulation. Cold Spring Harbor Laboratory Press Cold Spring Harbor, NY 743–69

    Google Scholar 

  40. CA Bondy H Werner CT Roberts SuffixJr D. LeRoith (1990) ArticleTitleCellular pattern of insulin-like growth factor I (IGF-I) and type I IGF gene expression in early organo-genesis: Comparison with IGF-II gene expression Clinical & Experimental Metastasis 4 1386–98

    Google Scholar 

  41. R Ammendola M Mesuraca T Russo F. Cimino (1992) ArticleTitleSp1 DNA binding efficiency is highly reduced in nuclear extracts from aged rat tissues Clinical & Experimental Metastasis 267 17944–8

    Google Scholar 

  42. K Xie D Wei Q Shi S. Huang (2004) ArticleTitleConstitutive and inducible expression and regulation of vascular endothelial growth factor Clinical & Experimental Metastasis 15 297–324

    Google Scholar 

Download references

Author information

Author notes

  1. Liwei Wang

    Present address: Shanghai East Hospital Cancer Center, Tongji University, Shanghai, The People’s Republic of China

Authors and Affiliations

  1. Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Yixing Jiang, Liwei Wang, Daoyan Wei, Xiangdong Le, James Yao, Jaffer Ajani, James L. Abbruzzese & Keping Xie

  2. Departments of Neurosurgery, The University of Texas, USA

    Weida Gong & Suyun Huang

  3. Departments of Cancer Biology, The University of Texas, MD, Anderson Cancer Center, Houston, Texas, USA

    Keping Xie

Authors
  1. Yixing Jiang
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  2. Liwei Wang
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  3. Weida Gong
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  4. Daoyan Wei
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  9. Suyun Huang
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  10. Keping Xie
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Corresponding author

Correspondence to Keping Xie.

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Jiang, Y., Wang, L., Gong, W. et al. 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. Clin Exp Metastasis 21, 755–764 (2005). https://doi.org/10.1007/s10585-005-1198-2

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  • DOI: https://doi.org/10.1007/s10585-005-1198-2

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