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Growth regulation of rabbit gastric epithelial cells and protooncogene expression

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Abstract

We recently developed a primary culture system for gastric epithelial cells from adult rabbits that allows the investigation of growth regulation at the cellular level. In this study, we demonstrated that epidermal growth factor (EGF), insulin, and dibutyryl adenosine 3′,5′-cyclic monophosphate (dBcAMP) all stimulated cell proliferation. Insulin and dB-cAMP potentiated the stimulation of cell proliferation by EGF, while transforming growth factor-β1 (TGF-β1) inhibited it. Expression of c-fos and c-myc was induced in response to the stimulation by these growth regulators, but the degree of expression did not necessarily correlate with the effects of these agents on cell proliferation. In conclusion, EGF, insulin, and dBcAMP were positive growth regulators, while TGF-β1 was a negative regulator in gastric epithelial cells. These growth modulators may exert their effects by distinct pathways from a standpoint of the expression of c-fos and c-myc.

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References

  1. Gregory H, Walsh S, Hopkins C: The identification of urogastrone in serum, saliva and gastric juice. Gastroenterology 77:313–328, 1979

    Google Scholar 

  2. Konturek S, Dembinski A, Warzecha Z, Brzozowski T, Gregory H: Role of epidermal growth factor in healing of chronic gastrointestinal ulcers in rats. Gastroenterology 94:1300–1307, 1988

    Google Scholar 

  3. Wright N, Pike C, Elia G: Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 343:82–85, 1990

    Google Scholar 

  4. Tarnawski A, Stachura J, Durbin T, Sarfeh I, Gergely H: Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats. Gastroenterology 102:695–698, 1992

    Google Scholar 

  5. Polk WJ, Dempsey P, Russell W, Brown P, Beauchamp R, Barnard J, Coffey RJ: Increased production of transforming growth factor-a following acute gastric injury. Gastroenterology 102:1467–1474, 1992

    Google Scholar 

  6. Rozengurt E: Early signals in the mitogenic response. Science 234:161–166, 1986

    Google Scholar 

  7. Müller 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 

  8. Yoshida K, Tsuda T, Matsumura T, Tsujino T, Hattori T, Ito H, Tahara E: Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas. Virchows Arch B Cell Pathol 57:285–290, 1989

    Google Scholar 

  9. Yoshida K, Yasui W, Ito H, Tahara E: Growth factors in progression of human esophageal and gastric carcinomas. Exp Pathol 40:291–300, 1990

    Google Scholar 

  10. Tahara E: Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 116:121–131, 1990

    Google Scholar 

  11. Ito M, Yasui W, Nakayama H, Yokozaki H, Ito H, Tahara E: Reduced levels of transforming growth factor-beta type I receptor in human gastric carcinomas. Jpn J Cancer Res 83:86–92, 1992

    Google Scholar 

  12. Kim S, Beauchamp R, Townsend CJ, Thompson J: Vasoactive intestinal polypeptide inhibits c-myc expression and growth of human gastric carcinoma cells. Surgery 110:270–276, 1991

    Google Scholar 

  13. Takanashi A, Yasui W, Yoshida K, Yokozaki H, Saito D, Abe K, Urakami K, Miki K, Tahara E: Inhibitory effect of 8-chloro-cyclic adenosine 3′,5′-monophosphate on cell growth of gastric carcinoma cell lines. Jpn J Cancer Res 82:325–331, 1991

    Google Scholar 

  14. Shibuya M, Yokota J, Ueyama Y: Amplification and expression of a cellular oncogene (c-myc) in human gastric adenocarcinoma cells. Mol Cell Biol 5:414–418, 1985

    Google Scholar 

  15. Yanagihara K, Seyama T, Tsumuraya M, Kamada N, Yokoro K: Establishment and characterization of human signet ring cell gastric carcinoma cell lines with amplification of the c-myc oncogene. Cancer Res 51:381–386, 1991

    Google Scholar 

  16. Ota S, Terano A, Hiraishi H, Mutoh H, Nakada R, Hata Y, Shiga J, Sugimoto T: A monolayer culture of gastric mucous cells from adult rabbits. Gastroenterol Jpn 25:1–7, 1990

    Google Scholar 

  17. Ota S, Hiraishi H, Terano A, Mutoh H, Kurachi Y, Shimada T, Ivey K, Sugimoto T: Effect of adenosine and adenosine analogs on [14C]aminopyrine accumulation by rabbit parietal cells. Dig Dis Sci 34:1882–1889, 1989

    Google Scholar 

  18. Terano A, Ivey K, Stachura J, Sekhon S, Hosojima H, McKenzie WJ, Krause W, Wyche J: Cell culture of rat gastric fundic mucosa. Gastroenterology 83:1280–1291, 1982

    Google Scholar 

  19. Ryseck R, Hirai S, Yaniv M, Bravo R: Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature 334:535–537, 1988

    Google Scholar 

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

    Google Scholar 

  21. Myhre E: Regeneration of the fundic mucosa in rats. Arch Pathol 70:476–485, 1960

    Google Scholar 

  22. Heldin C, Westermark B: Growth factors: Mechanism of action and relation to oncogenes. Cell 37:9–20, 1984

    Google Scholar 

  23. Matsuoka K, Tanaka M, Mitsui Y, Murota S: Cultured rabbit gastric epithelial cells producing prostaglandine I2. Gastroenterology 84:498–505, 1983

    Google Scholar 

  24. Chen M, Lee A, Soll A: Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor-α and insulinlike growth factor I. J Clin Invest 87:1716–1723, 1991

    Google Scholar 

  25. Sporn M, Roberts A, Wakefield L, Assoian R: Transforming growth factor-β: Biological function and chemical structure. Science 233:532–534, 1986

    Google Scholar 

  26. Bennett C, Paterson I, Corbishley C, Luqmani Y: Expression of growth factor and epidermal growth factor receptor encoded transcripts in human gastric tissues. Cancer Res 49:2104–2111, 1989

    Google Scholar 

  27. Sporn M, Roberts A: Peptide growth factors and inflammation, tissue repair, and cancer. J Clin Invest 78:329–332, 1986

    Google Scholar 

  28. Cromack D, Sporn M, Roberts A, Merino M, Dart L, Norton J: Transforming growth factor-β levels in rat wound chambers. J Surg Res 42:622–628, 1987

    Google Scholar 

  29. Mustoe T, Pierce G, Thomason A, Gramates P, Sporn M, Deuel T: Accelerated healing of incisional wounds in rats induced by transforming growth factor-β. Science 237:1333–1336, 1987

    Google Scholar 

  30. Pierce G, Mustoe T, Lingelbach J, Masakowski V, Gramates P, Deuel T: Transforming growth factor-β reverses the glucocorticoid-induced wound-healing deficit in rats: Possible regulation in macrophages by platelet-derived growth factor. Proc Natl Acad Sci USA 86:2229–2233, 1989

    Google Scholar 

  31. Pierce G, Mustoe T, Lingelbach J, Masakowski V, Griffin G, Senior R, Deuel T: Platelet-derived growth factor and transforming growth factor-β enhance tissue repair activities by unique mechanisms. J Cell Biol 109:429–440, 1989

    Google Scholar 

  32. Mustoe T, Pierce G, Morishima C, Deuel T: Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model. J Clin Invest 87:694–703, 1991

    Google Scholar 

  33. Mustoe T, Landes A, Cromack D, Mistry D, Griffin A, Deuel T, Pierce G: Differential acceleration of healing of surgical incisions in the rabbit gastrointestinal tract by platelet-derived growth factor and transforming growth factor, type beta. Surgery 108:324–330, 1990

    Google Scholar 

  34. Zendegui J, Inman W, Carpenter G: Modulation of the mitogenic response of an epidermal growth factor-dependent keratinocyte cell line by dexamethasone, insulin, and transforming growth factor-β. J Cell Physiol 136:257–265, 1988

    Google Scholar 

  35. Russell W: Transforming growth factor beta (TGF-β) inhibits hepatocyte DNA synthesis independently of EGF binding and EGF receptor autophosphorylation. J Cell Physiol 135:253–261, 1988

    Google Scholar 

  36. Logsdon C, Keyes L, Beauchamp R: Transforming growth factor-β1 (TGF-β1) inhibits pancreatic acinar cell growth. Am J Physiol 262:G364-G368, 1992

    Google Scholar 

  37. Green H: Cyclic AMP in relation to proliferation of the epidermal cell: A new view. Cell 15:801–811, 1978

    Google Scholar 

  38. Taylor-Papadimitriou J, Purkis P, Fentiman I: Cholera toxin and analogues of cyclic AMP stimulate the growth of cultured human mammary epithelial cells. J Cell Physiol 102:317–321, 1980

    Google Scholar 

  39. Imagawa W, Bandyopadhyay G, Wallace D, Nandi S: Growth stimulation by PGE2 and EGF activates cyclic AMP-dependent and -independent pathways in primary cultures of mouse mammary epithelial cells. J Cell Physiol 135:509–515, 1988

    Google Scholar 

  40. Grove R, Pratt R: Influence of epidermal growth factor and cyclic AMP on growth and differentiation of palatal epithelial cells in culture. Dev Biol 106:427–437, 1984

    Google Scholar 

  41. Willey J, Laveck M, McClendon I, Lechner J: Relationship of ornithin decarboxylase activity and cAMP metabolism to proliferation of normal human bronchial epithelial cells. J Cell Physiol 124:207–212, 1985

    Google Scholar 

  42. Chen MC, Lee AT, Karnes WE, Avedian D, Martin M, Sorvillo JM, Soll AH: Paracrine control of gastric epithelial cell growth in culture by transforming growth factor-α. Am J Physiol 264:G390-G396, 1993

    Google Scholar 

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

    Google Scholar 

  44. Hedlin N, Westermark B: Epidermal growth factor, but not thyrotropin, stimulates the expression of c-fos and c-myc messenger ribonucleic acid in porcine thyroid follicle cells in primary culture. Endocrinology 122:1042–1046, 1988

    Google Scholar 

  45. Larsson S, Hultgårdh-Nilsson A, Kölare S, Luthman J, Sejersen T, Apiria A: Serum factors induce c-fos expression and rapid cell proliferation in adolescent but not in infant rat proximal tubule cells. Pediatr Res 29:263–267, 1991

    Google Scholar 

  46. Jouvenot M, Pellerin I, Maréchal G, Royez M, Ordener C, Alkhalaf M, Adessi G: Regulation of c-fos expression in primary culture of guinea pig glandular epithelial cells stimulated by growth factors and estradiol. Reprod Nutr Dev 30:455–458, 1990

    Google Scholar 

  47. Jouvenot M, Pellerin I, Alkhalaf M, Marechal G, Royez M, Adessi G: Effects of 17β-estradiol and growth factors on c-fos gene expression in endometrial epithelial cells in primary culture. Mol Cell Endocrinol 72:149–157, 1990

    Google Scholar 

  48. Chiu R, Boyle W, Meek J, Smeal T, Hunter T, Karin M: The c-fos protein interacts with c-jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54:541–552, 1988

    Google Scholar 

  49. Kelly K, Cochran B, Stiles C, Leder P: Cell-specific regulation of the c-myc gene by the lymphocyte mitogens and platelet-derived growth factor. Cell 35:603–610, 1983

    Google Scholar 

  50. Koda T, Matsushima S, Sasaki A, Danjo Y, Kakiuma M: c-myc gene amplification in primary stomach cancer. Jpn J Cancer Res 76:551–554, 1985

    Google Scholar 

  51. Nomura N, Yamamoto T, Toyoshima K, Ohami H, Akimaru K, Sasaki S, Nakagami Y, Kanauchi H, Shoji T, Hiraoka Y, Matsui M, Ishizaki R: DNA amplification of the c-myc and c-erbB-1 genes in a human stomach cancer. Jpn J Cancer Res 77:1188–1192, 1986

    Google Scholar 

  52. Ito T, Hayashi N, Sasaki Y, Morita Y, Kawano S, Fusamoto H, Sato N, Tohyama M, Kamada T: Sequential protooncogene expression during regeneration in rat stomach. Gastroenterology 98:1525–1531, 1990

    Google Scholar 

  53. Kruijer W, Cooper J, Hunter T, Verma I: Platelet-derived growth factor induces rapid but transient expression of the c-fos gene and protein. Nature 312:711–716, 1984

    Google Scholar 

  54. Takehara K, LeRoy E, Grotendorst G: TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell 49:415–422, 1987

    Google Scholar 

  55. Coffey RJ, Bascom C, Sipes N, Graves-Deal R, Weissman B, Moses H: Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor-β. Mol Cell Biol 8:3088–3093, 1988

    Google Scholar 

  56. Pietenpol J, Holt J, Stein R, Moses H: Transforming growth factor-β1 suppression of c-myc gene transcription: Role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci USA 87:3758–3762, 1990

    Google Scholar 

  57. McMahon J, Richards W, del Campo A, Song M, Thorgeirsson S: Differential effects of transforming growth factor-β on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res 46:4665–4671, 1986

    Google Scholar 

  58. Mulder K, Zhong Q, Choi H, Humphrey L, Brattain M: Inhibitory effects transforming growth factor-β1 on mitogenic response, transforming growth factor-α, and c-myc in quiescent, well-differentiated colon carcinoma cells. Cancer Res 50:7581–7586, 1990

    Google Scholar 

  59. Fernandez-Pol J, Talked V, Klos D, Hamilton P: Suppression of the EGF-dependent induction of c-myc protooncogene expression by transforming growth factor-β in a human breast carcinoma cell line. Biochem Biophys Res Commun 144:1197–1205, 1987

    Google Scholar 

  60. Mechta F, Piette J, Hirai S, Yaniv M: Stimulation of protein kinase C or protein kinase A mediated signal transduction pathways shows three modes of response among serum inducible genes. New Biol 1:297–304, 1989

    Google Scholar 

  61. Ran W, Dean M, Levine R, 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 

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Yoshiura, K., Ota, S., Terano, A. et al. Growth regulation of rabbit gastric epithelial cells and protooncogene expression. Digest Dis Sci 39, 1454–1463 (1994). https://doi.org/10.1007/BF02088048

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