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Expression of EGF-Receptor Related Protein (ERRP) Decreases in Gastric Mucosa During Aging and Carcinogenesis

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Abstract

Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases in this tissue during this period. The latter is accompanied by a concomitant reduction in the amount of TGF-α bound to ERRP. In contrast, the amount of TGF-α bound to EGFR is found to be higher in the gastric mucosa of aged than in young rats. This is accompanied by a concomitant rise in EGFR levels. In the gastric mucosa, EGFR and ERRP are found to be colocalized. Gastric adenocarcinoma in humans, which has been shown to be associated with increased activation of EGFR, shows a substantial reduction in ERRP expression, when compared with benign tissues. We conclude that increased activation of EGFR in the gastric mucosa during aging and carcinogenesis may partly be due to the loss of ERRP.

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References

  1. Candena DL, Gill GN: Receptor tyrosine kinases. FASEB J 6: 2332-2337, 1992

    Google Scholar 

  2. Glenney JR: Tyrosine-phosphorylated proteins: mediators of signal transduction from the tyrosine kinases. Biochim Biophys Acta 1134:113-127, 1992

    Google Scholar 

  3. Hunter T, Cooper JA: Protein tyrosine kinases. Annu Rev Biochem 54:897-930, 1985

    Google Scholar 

  4. Joensuu HJ, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman SL, Capdeville R, Dimitrijevic S, Druker B, Demetri GD: Effect of the tyrosine kinase inhibitor ST1571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052-1056, 2000

    Google Scholar 

  5. Yarden Y, Ullrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem 57:443-487, 1987

    Google Scholar 

  6. Barnard JA, Beauchamp J, Russell WE, Dubois RN, Coffey RJ: Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology 108:564-580, 1995

    Google Scholar 

  7. Garcia I, Vizoso F, Andicoechea A, Raigoso P, Verez P, Alexandre E, Garcia-Muniz JL, Allende MT: Clinical significance of epidermal growth factor receptor content in gastric cancer. Int J Biol Marker 16:183-188, 2001

    Google Scholar 

  8. Gullick WJ: Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull 47:87-98, 1991

    Google Scholar 

  9. Khasharyarsha K, Schirrmacher V, Lichtner RB: EGF-receptor in neoplasia. Cancer Metastasis Rev 12:255-274, 1993

    Google Scholar 

  10. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi H, Angeletti CA, Pingitore R, Pepe S, Basolo F, Bevilacqua G: Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 31A: 178-183, 1995

    Google Scholar 

  11. Nicholson S, Richanrs J, Sainsbury C, Hlacrow P, Kelly P, Angus B, Wright C, Henry J, Farndon JR, Harris AL: Epidermal growth factor receptor (EGFr); results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup. Br J Cancer 63:146-150, 1991

    Google Scholar 

  12. Grandis JR, Tweardy DJ, Melhem MF: Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res 4:13-20, 1998

    Google Scholar 

  13. Malecka-Panas E, Kordek R, Biernat W, Tureaud J, Liberski PP, Majumdar APN: Differential activation of total and EGF receptor tyrosine kinase in the rectal mucosa in patients with adenomatous polyps, ulcerative colitis and colon cancer. hepatogastroenterology 44:435-440, 1997

    Google Scholar 

  14. Atillasoy E, Holt PR: Gastrointestinal proliferation and aging. J Gerontol 48: B43-B49, 1993

    Google Scholar 

  15. Jaszewski R, Ehrinpreis MN, Majumdar APN: Aging and cancer of the stomach and colon. Front Biosci 4:322-328, 1999

    Google Scholar 

  16. Majumdar, APN, Jaszewski R, Dubick MA: Effect of aging on the gastroiintestinal tract and pancreas. Proc Soc Exp Biol Med 215:134-144, 1997

    Google Scholar 

  17. Holt PR, Yeh K-Y: Colonic proliferation is increased in senescent rats. Gastroenterology 95:1556-1563, 1988

    Google Scholar 

  18. Holt PR, Yeh K-Y, Kolter DP: Altered controls of proliferation in proximal small intestine of the senescent rat. Proc Natl Acad Sci USA 85:2771-2775, 1988

    Google Scholar 

  19. Holt PR, Yeh K-Y: Small intestinal crypt cell proliferation rates are increased in senescent rats. J Gerontol 44:B9-B14, 1989

    Google Scholar 

  20. Majumdar APN, Arlow FL: Aging: altered resposiveness of gastric mucosa to epidermal growth factor. Am J Physiol Gastrointest Liver Physiol 257:G554-560, 1989

    Google Scholar 

  21. Majumdar APN, Jasti S, Hatfield JS, Tureaud J, Fligiel SEG: Morphological and biochemical changes in gastric mucosa of aged rats. Dig Dis Sci 35:1364-1370, 1990

    Google Scholar 

  22. Xiao Z-Q, Moragoda L, Jaszewski R, Hatfield JA, Fligiel SEG, Majumdar APN: Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa. Mech Ageing Dev 122:1849-1864, 2001

    Google Scholar 

  23. Turner JR, Liu L, Fligiel SEG, Jaszewski R, Majumdar APN: Aging alters gastric mucosal responses to epidermal growth factor and transforming growth factor α. Am J Physiol Gastrointest Liver Physiol 278:G805-G810, 2000

    Google Scholar 

  24. Tureaud J, Sarkar FH, Fligiel SEG; Kulkarni S, Jaszewski R, Reddy K, Yu Y, Majumdar APN: Increased expression of EGFR in gastric mucosa of aged rats. Am J Physiol Gastrointest Liver Physiol 273:G389-G398, 1997

    Google Scholar 

  25. Xiao Z-Q, Majumdar APN: Increased in vitro activation of EGFR by membrane-bound EGF from gastric and colonic mucosa of aged rats. Am J Physiol Gastrointest Liver Physiol 281:G111-G116, 2001

    Google Scholar 

  26. Xiao Z-Q, Majumdar APN: Induction of transcriptional activity of AP-1 and NF-κB in the gastric mucosa during aging. Am J Physiol Gastrointest Liver Physiol 278:G855-G865, 2000

    Google Scholar 

  27. Yu, Y, Rishi AK, Turner JR, Liu D, Black ED, Moshier JA, Majumdar APN: Cloning of a novel EGFR-related peptide: a putative negative regulator of EGFR. Am J. Physiol Cell Physiol 280:C1083-C1089, 2001

    Google Scholar 

  28. Feng J, Adsay NV, Kruger M, Majumdar APN, Sarkar FH: Expression of ERRP in normal and neoplastic pancreata and its relationship to clinicopathological parameters in pancreatic adenocarcinoma. Pancreas 25:342-349, 2002

    Google Scholar 

  29. Moragoda L, Yu Y, Rishi AK, Xiao Z-Q, Majumdar APN: Inhibition of EGFR Activation and Cell Proliferation by ERRP: a negative regulator of EGFR. Gastroenterology 122:S852, 2002

    Google Scholar 

  30. Bennett C, Paterson IM, Corbishley CM, Luqmani YA: Expression of growth factor and epidermal growth factor receptor encoded transcript in human gastric tissues. Cancer Res 49:2104-2111, 1989

    Google Scholar 

  31. Majumdar APN, Johnson LR: Gastric mucosal cell proliferation during development in rats and effects of pentagastrin. Am J Physiol Gastrointest Liver Physiol 242:G135-G139, 1982

    Google Scholar 

  32. Lipkin M: Biomarker of increased susceptibility to gastrointestinal cancer: their development and application to studies of cancer prevention. Gastroenterology 92:1083-1086, 1987

    Google Scholar 

  33. Moragoda L, Jaszewski R, Kulkarni P, Majumdar APN: Age-associated loss of heterozygosity of tumor suppressor genes in the gastric mucosa of humans. Am J Physiol Gastrointest Liver Physiol 282:G932-G936, 2002

    Google Scholar 

  34. Masaki T, Hatanaka Y, Nishika M, Tokuda M, Shiratori Y, Reginfo W, Omata M: Activation of epidermal growth factor receptor kinase in gastric carcinoma: a preliminary study. Am J Gastroenterol 95:2135-2136, 2001

    Google Scholar 

  35. Slesak B, Harlozinska A, Porebska I, Bojarowski T, Lapinska J, Rzesutko J, Wajnar M: Expression of epidermal growth factor receptor family proteins (EGFR, c-erbB-2 and c-erbB-3) in gastric cancer and chronic gastritis. Anticancer Res 8:2727-2732, 1998.

    Google Scholar 

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Authors and Affiliations

  1. Veterans Affairs Medical Center, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    James S. Hatfield, Edi Levi & Richard Jaszewski

  2. Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    Adhip P.N. Majumdar, Eva M. Schmelz, Omer Kucuk & Fazlul H. Sarkar

  3. Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    Adhip P.N. Majumdar, Jianhua Du & Kiran K. Nagothu

  4. Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    Adhip P.N. Majumdar

  5. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    Adhip P.N. Majumdar

  6. Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, 48201, USA

    Volkan Adsay

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  1. Adhip P.N. Majumdar
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Majumdar, A.P., Du, J., Hatfield, J.S. et al. Expression of EGF-Receptor Related Protein (ERRP) Decreases in Gastric Mucosa During Aging and Carcinogenesis. Dig Dis Sci 48, 856–864 (2003). https://doi.org/10.1023/A:1023078924686

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