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Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease

  • Intestinal Disorders, Inflammatory Bowel Disease, Immunology, and Microbiology
  • Published:
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Abstract

Protooncogenes are cell cycle-related genes that are involved in cell growth or proliferation. Alterations in the level of expression of these genes, or expression of aberrant gene products, have been observed in tumors and precancerous conditions. To determine if expression of these genes is altered in patients with inflammatory bowel disease (IBD)-who are at risk for development of colon cancer—we assayed transcripts of 15 protooncogenes in colonic epithelial cells of IBD patients and controls. Nine, of these genes (H-ras, c-myc, c-fos, c-jun, junB, N-myc, c-abl, c-yes, andp53) were expressed in epithelial cells, whereas two (RB1 and N-ras) were not. Expression of four other genes (c-src, K-ras, c-raf and c-myb) was observed, but the intensity of these bands was too low for densitometric analysis. The steady-state levels of transcripts of H-ras and five nuclear protooncogenes (c-myc, c-fos, c-jun, junB, and N-myc) were lower in epithelial cells from involved or uninvolved IBD samples than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. The level of c-fos mRNA was two-to threefold higher in involved than in uninvolved areas of the colons of two ulcerative colitis (UC) patients, but not in one Crohn's disease (CD) patient. Message abundance of c-abl transcripts was two-to threefold lower in UC epithelial cells than in either the CD or control samples. The steady-state level of c-yes-encoded mRNA was considerably higher in IBD patients resected for colon cancer than in patients resected for active chronic IBD or in controls. The level ofp53 message was constant in these samples. Increased levels of c-fos mRNA in involved UC relative to uninvolved, UC may be related to the disease process. Decreased expression of c-abl transcripts in UC may be a diagnostic marker for UC and may be related to the rate of cell turnover in these diseases. Enhanced expression of c-yes in IBD patients with tumors compared to active chronic IBD and controls suggests that expression of this gene may be a marker for development of colon cancer in IBD.

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References

  1. Macdermott RP, Stenson WF: Alterations of the immune system in ulcerative colitis and Crohn's disease. Adv Immunol 42:285–328, 1988

    Google Scholar 

  2. Collins RH Jr, Feldman M, Fordtran JS: Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis: A critical review. N Engl J Med 316:1654–1658, 1987

    Google Scholar 

  3. Alexander RJ, Panja A, Kaplan-Liss E, Mayer L, Raicht RF: Expression of growth factor receptor-encoded mRNA is altered in inflammatory bowel disease. Dig Dis Sci 40:485–494, 1995

    Google Scholar 

  4. Shanahan F, Targan S: Mechanisms of tissue injury in inflammatory bowel disease.In Current Topics in Gastroenterology: Inflammatory Bowel Disease, RP MacDermott, WF Stenson (eds). New York, Elsevier, 1982, pp 77–93

    Google Scholar 

  5. Bishop JM: The molecular genetics of cancer. Science 235:305–311, 1987

    Google Scholar 

  6. Druker BJ, Mamon HJ, Roberts TM: Oncogenes, growth factors, and signal transduction. N Engl J Med 321:1383–1391, 1989

    Google Scholar 

  7. Mayer L, Eisenhardt D: Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease. J Clin Invest 86:1255–1260, 1990

    Google Scholar 

  8. Chomczynski P, Sacchi N: Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159, 1987

    Google Scholar 

  9. Delorbe WJ, Luciw PA, Goodman HM, Varmus HE, Bishop JM: Molecular cloning and characterization of avian sarcoma virus circular DNA. J Virol 36:50–61, 1980

    Google Scholar 

  10. Wang JYJ, Ledley F, Goff S, Lee R, Groner Y, Baltimore D: The mouse c-abl locus: Molecular cloning and characterization. Cell 36:349–356, 1984

    Google Scholar 

  11. Sukegawa J, Semba K, Yamanashi Y, Nishizawa M, Miyajima N, Yamamoto, T, Toyoshima K: Characterization of cDNA clones for the human c-yes gene. Mol Cell Biol 7:41–47, 1987

    Google Scholar 

  12. Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M: Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300:762–765, 1982

    Google Scholar 

  13. McCoy MS, Bargmann CI, Weinberg RA: Human colon carcinoma Ki-ras-2 oncogene and its corresponding protooncogene. Mol Cell Biol 4:1577–1582, 1984

    Google Scholar 

  14. Murray MJ, Cunningham JM, Parada LF, Dautry F, Lebowitz P, Weinberg, RA: The HL-60 transforming sequence: Aras oncogene coexisting with alteredmyc genes in hematopoietic tumors. Cell 33:749–757, 1983

    Google Scholar 

  15. Bonner TI, Oppermann H, Seeburg P, Kerby SB, Gunnell MA, Young AC, Rapp UR: The complete coding sequence of the humanraf oncogene and the corresponding structure of the c-raf-1 gene. Nucleic Acids Res 14:1009–1015, 1988

    Google Scholar 

  16. Dalla-Favera R, Martinotti S, Gallo RC, Erikson J, Croce CM: Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 219:963–967, 1983

    Google Scholar 

  17. Schwab M, Alitalo K, Klempnauer K-H, Varmus HE, Bishop JM, Gilbert F, Brodeur G, Goldstein M, Trent J: Amplified DNA with limited homology tomyc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 305:245–248, 1983

    Google Scholar 

  18. Bender TP, Kuchl WM: Murinemyb proto-oncogene mRNA: cDNA sequence and evidence for 5′ heterogeneity. Proc Natl Acad Sci USA 83:3204–3208, 1986

    Google Scholar 

  19. Miller AD, Curran T, Verma IM: c-fos protein can induce cellular transformation: A novel mechanism of activation of a cellular oncogene. Cell 36:51–60, 1984

    Google Scholar 

  20. Ryder K, Nathans D: Induction of proto-oncogene c-jun by serum growth factors. Proc Natl Acad Sci USA 85:8464–8467, 1988

    Google Scholar 

  21. Ryder K, Lau LF, Nathans D: A gene activated by growth factors is related to the oncogene v-jun. Proc Natl Acad Sci USA 85:1487–1491, 1988

    Google Scholar 

  22. Zakat-Houri R, Bienz-Tadmor B, Givol D, Oren M: Human p53 cellular tumor antigen: cDNA sequence and expression in COS cells. EMBO J 4:1251–1255, 1985

    Google Scholar 

  23. Friend SH, Bernards M, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646, 1986

    Google Scholar 

  24. Fort P, Piechaczyk M, El Sabrouty S, Dani C, Jeanteur P, Blanchard JM: Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphatedehydrogenase multigenic family. Nucleic Acids Res 13:1431–1442, 1985

    Google Scholar 

  25. Aaronson SA: Growth factors and cancer. Science 254:1146–1153, 1991

    Google Scholar 

  26. Greenberg ME, Ziff EB: Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 311:433–438, 1984

    Google Scholar 

  27. Cochran BM, Zullo J, Verma IM, Stiles CD: Expression of the c-fos gene and of afos-related gene is stimulated by platelet derived growth factor. Science 226:1080–1082, 1984

    Google Scholar 

  28. Liboi E, Pelosi E, Testa U, Peschle C, Battista Rossi G: Proliferative response and oncogene expression induced by epidermal growth factor in EL2 rat fibroblasts. Mol Cell Biol 6:2275–2278, 1986

    Google Scholar 

  29. Reed JC, Alpers JD, Nowell PC, Hoover RG: Sequential expression of protooncogenes during lectin-stimulated mitogenesis of normal human lymphocytes. Proc Natl Acad Sci USA 83:3982–3986, 1986

    Google Scholar 

  30. Ran W, Dean M, Levine RA, Henkle C, Campisi J: Induction of c-fos and c-myc mRNA by epidermal growth factor or calcium ionophore is cAMP dependent. Proc Natl Acad Sci USA 83:8216–8220, 1986

    Google Scholar 

  31. Quantin B, Breathnach R: Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. Nature 334:538–539, 1988

    Google Scholar 

  32. Hanover SB: Corticosteroids.In Inflammatory Bowel Disease. G Jarnerot, J Lennard-Jones, S Truclove (eds), New York, Corona, 1992, pp 297–312

    Google Scholar 

  33. Muller R, Bravo R, Burckhardt J, Curran T: Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature 312:716–720, 1984

    Google Scholar 

  34. Rittling SR, Brooks KM, Cristofalo VJ, Baserga R: Expression of cell cycle dependent genes in young and senescent WI-38 fibroblasts. Proc Natl Acad Sci USA 83:3316–3320, 1986

    Google Scholar 

  35. Seshadr T, Campisi J: Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247:205–209, 1990

    Google Scholar 

  36. Macpherson AJS, Chester KA, Robson L, Bjarnason I, Malcolm ADB, Peters TJ: Increased expression of c-myc protooncogene in biopsies of ulcerative colitis and Crohn's colitis. Gut 33:651–656, 1992

    Google Scholar 

  37. Meltzer SJ, Zhou D, Weinstein WM: Tissue-specific expression of c-Ha-ras in premalignant gastrointestinal mucosae. Exp Mol Pathol 51:264–274, 1989

    Google Scholar 

  38. Friedman SL, Arthur AJP: Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. J Clin Invest 84:1780–1785, 1989

    Google Scholar 

  39. Witte ON: Role of theBCR-ABL oncogene in human leukemia. Cancer Res 53:485–489, 1993

    Google Scholar 

  40. Wang JYJ, Baltimore D: Cellular RNA homologous to the Abelson murine leukemia virus transforming gene: Expression and relationship to the viral sequence. Mol Cell Biol 3:773–779, 1983

    Google Scholar 

  41. Renshaw MW, Capozza MA, Wang JYJ: Differential expression of type-specific c-abl mRNAs in mouse tissues and cell lines. Mol Cell Biol 8:4547–4551, 1988

    Google Scholar 

  42. Sawyers CL, McLaughlin J, Goga A, Havlik M, Witte O: The nuclear tyrosine kinase c-abl negatively regulates cell growth. Cell 77:121–134, 1994

    Google Scholar 

  43. Sudol M, Hanafusa H: Cellular proteins homologous to the viralyes gene. Mol Cell Biol 6:2839–2846, 1986

    Google Scholar 

  44. Yoshida M, Kawai S, Toyoshima K: Uninfected avian cells contain structurally unrelated progenitors of viral sarcoma genes. Nature 287:653–654, 1980

    Google Scholar 

  45. Shibuya M, Hanafusa H, Balduzzi PC: Cellular sequences related to three new one-genes of avian sarcoma virus (fps. yes. andros) and their expression in normal and transformed cells. J Virol 43:143–152, 1982

    Google Scholar 

  46. Semba K, Yamanashi Y, Nishizawa M, Sukegawa J, Yoshida, M, Sasaki M, Yamamoto T, Toyoshima K: Location of the c-yes gene on the human chromosome and its expression in various tissues. Science 227:1038–1040, 1985

    Google Scholar 

  47. Park J, Meisler AI, Cartwright CA: c-yes tyrosine kinase activity in human colon carcinoma. Oncogene 8:2627–2635, 1993

    Google Scholar 

  48. Pena SV, Melhem MF, Meisler AI, Cartwright CA: Elevated c-yes tyrosine kinase activity in premalignant lesions of the colon. Gastroenterology 108:117–124, 1995

    Google Scholar 

  49. Cartwright CA, Coad CA, Egbert BM: Elevated c-src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. J Clin Invest 93:509–515, 1994

    Google Scholar 

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Authors and Affiliations

  1. Department of Veterans Affairs Medical Center, Research Service 151A, 423 East 23rd Street, 10010, New York, New York

    Richard J. Alexander PhD, Asit Panja MD, Evonne Kaplan-Liss BA, Lloyd Mayer MD & Robert F. Raicht MD

  2. Department of Medicine, New York University Medical Center, 10016, New York, New York

    Richard J. Alexander PhD, Asit Panja MD, Evonne Kaplan-Liss BA, Lloyd Mayer MD & Robert F. Raicht MD

  3. Division of Clinical Immunology, Mount Sinai Medical Center, 10029, New York, New York

    Richard J. Alexander PhD, Asit Panja MD, Evonne Kaplan-Liss BA, Lloyd Mayer MD & Robert F. Raicht MD

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  1. Richard J. Alexander PhD
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  2. Asit Panja MD
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  3. Evonne Kaplan-Liss BA
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  4. Lloyd Mayer MD
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  5. Robert F. Raicht MD
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Additional information

This research was supported in part by grants (to L.M.) Al-23504, AI-24671, and DK-44156 from the National Institutes of Health, and by grants (to R.F.R.) from the Department of Veterans Affairs and from the Division of Sponsored Research, Marion Merrell Dow, Inc.

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Alexander, R.J., Panja, A., Kaplan-Liss, E. et al. Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease. Digest Dis Sci 41, 660–669 (1996). https://doi.org/10.1007/BF02213120

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  • DOI: https://doi.org/10.1007/BF02213120

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