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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1993 Aug;84(8):879–884. doi: 10.1111/j.1349-7006.1993.tb02061.x

Expression of Amphiregulin, a Novel Gene of the Epidermal Growth Factor Family, in Human Gastric Carcinomas

Yasuhiko Kitadai 1,2, Wataru Yasui 1, Hiroshi Yokozaki 1, Hiroki Kuniyasu 1, Ayse Ayhan 1, Ken Haruma 2, Goro Kajiyama 2, Gibbes R Johnson 3, Eiichi Tahara 1,
PMCID: PMC5919273  PMID: 8407551

Abstract

The expression of mRNA for amphiregulin (AR), a novel gene of the epidermal growth factor family, was examined in 8 human gastric carcinoma cell lines and 32 gastric carcinoma tissues as well as corresponding normal mucosa. Of the 8 gastric carcinoma cell lines, 7 expressed 1.4 kb AR mRNA at various levels. The expression of AR mRNA by TMK‐1 and MKN‐28 cells was increased by treatment with epidermal growth factor or transforming growth factor α. In surgical cases, all the gastric carcinoma tissues and their adjacent normal mucosa expressed AR mRNA. Interestingly, 20 (62.5%) out of 32 tumors expressed AR mRNA at higher levels than their corresponding normal mucosas (tumor/normal ≥1.2). No obvious correlation was observed between the AR mRNA levels and the histological types or tumor staging of gastric carcinoma. Immunohistochemically, AR protein was localized to the cytoplasm and/or nucleus in tumor cells. These results suggest that AR produced by tumor cells may be involved in the pathogenesis and/or progression of human gastric carcinoma.

Keywords: Amphiregulin, Gastric carcinoma, Growth factor

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References

  • 1.Sporn , M. B. and Roberts , A. B.Autocrine growth factors and cancer . Nature , 313 , 745 – 747 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 2.Sporn , M. B. and Roberts , A. B.Peptide growth factors are multifunctional . Nature , 332 , 217 – 218 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 3.Tahara , E.Growth factors and oncogenes in human gastrointestinal carcinomas . J. Cancer Res. Clin. Oncol. , 116 , 121 – 131 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 4.Yoshida , K. , Kyo , E. , Tsujino , T. , Sano , T. , Niimoto , M. and Tahara , E.Expression of epidermal growth factor, transforming growth factor‐α and their receptor genes in human gastric carcinomas; implication for autocrine growth . Jpn. J. Cancer Res. , 81 , 43 – 51 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Yasui , W. , Sumiyoshi , H. , Hata , J. , Kameda , T. , Ochiai , A. , Ito , H. and Tahara , E.Expression of epidermal growth factor receptor in human gastric and colonic carcinomas . Cancer Res. , 48 , 137 – 141 ( 1988. ). [PubMed] [Google Scholar]
  • 6.Tahara , E. , Sumiyoshi , H. , Hata , J. , Yasui , W. , Taniyama , K. , Hayashi , T. , Nagae , S. and Sakamoto , S.Human epidermal growth factor in gastric carcinoma as a biologic marker of high malignancy . Jpn. J. Cancer Res. , 77 , 145 – 152 ( 1986. ). [PubMed] [Google Scholar]
  • 7.Ciccodicola , A. , Dono , R. , Obici , S. , Simeone , A. , Zollo , M. and Persico , M. G.Molecular characterization of a gene of the ‘EGF family’ expressed in undifferentiated human NTERA2 teratocarcinoma cells . EMBO J. , 8 , 1987 – 1991 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Shoyab , M. , McDonald , V. L. , Bradley , J. G. and Todaro , G. J.Amphiregulin: a bifunctional growth‐modulating glycoprotein produced by the phorbol 12‐myristate 13‐acetate‐treated human breast adenocarcinoma cell line MCF‐7 . Proc. Natl. Acad. Sci. USA , 85 , 6528 – 6532 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Higashiyama , S. , Abraham , J. A. , Miller , J. , Fiddes , J. C. and Klagsbrun , M.A heparin‐binding growth factor secreted by macrophage‐like cells that is related to EGF . Science , 251 , 936 – 939 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 10.Higashiyama , S. , Lau , K. , Besner , G. E. , Abraham , J. A. and Klagsbrun , M.Structure of heparin‐binding EGF‐like growth factor . J. Biol Chem. , 267 , 6205 – 6212 ( 1992. ). [PubMed] [Google Scholar]
  • 11.Shoyab , M. , Plowman , G. D. , McDonald , V. L. , Bradley , J. G. and Todaro , G. J.Structure and function of human amphiregulin: a member of the epidermal growth factor family . Science , 243 , 1074 – 1076 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 12.Johnson , G. R. , Kannan , B. , Shoyab , M. and Stromberg , K.Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p188erbB2 . J. Biol. Chem. , 268 , 2924 – 2931 ( 1993. ). [PubMed] [Google Scholar]
  • 13.Plowman , G. D. , Green , J. M. , McDonald , V. L. , Neubauer , M. G. , Disteche , C. M. , Todaro , G. J. and Shoyab , M.The amphiregulin gene encodes a novel epidermal growth factor‐related protein with tumorinhibitory activity . Mol. Cell. Biol. , 10 , 1969 – 1981 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Johnson , G. R. , Saeki , T. , Auersperg , N. , Gordon , A. W. , Shoyab , M. , Salomon , D. S. and Stromberg , K.Response to and expression of amphiregulin by ovarian carcinoma and normal ovarian surface epithelial cells: nuclear localization of endogenous amphiregulin . Biochem. Biophys. Res. Commun. , 180 , 481 – 488 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 15.Johnson , G. R. , Saeki , T. , Gordon , A. W. , Shoyab , M. , Salomon , D. S. and Stromberg , K.Autocrine action of amphiregulin in a colon carcinoma cell line and immunocytochemical localization of amphiregulin in human colon . J. Cell Biol. , 118 , 741 – 751 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ochiai , A. , Yasui , W. and Thara , E.Growth‐promoting effect of gastrin in human gastric carcinoma cell line TMK‐1 . Jpn. J. Cancer Res. , 76 , 1064 – 1071 ( 1985. ). [PubMed] [Google Scholar]
  • 17.Yanagihara , K. , Seyama , T. , Tsumuraya , M. , Kamada , N. and 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. ). [PubMed] [Google Scholar]
  • 18.Maniatis , T. , Fritsch , E. F. and Sambrook , J. “ Molecular Cloning: A Laboratory Manual ,” 8th Ed. , pp. 187 – 210 ( 1984. ). Cold Spring Harbor Laboratory; , New York. [Google Scholar]
  • 19.Yoshida , K. , Tsuda , T. , Matsumura , T. , Tsujino , T. , Hattori , T. , Ito , H. and Tahara , E.Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas . Virchows Arch. B , 57 , 285 – 290 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 20.Yoshida , K. , Takanashi , A. , Kyo , E. , Ito , M. , Ito , H. , Niimoto , M. , Hattori , T. and Tahara , E.Epidermal growth factor induces the expression of its receptor gene in human gastric carcinoma cell line TMK‐1 . Jpn. J. Cancer Res. , 80 , 743 – 746 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Yoshida , K. , Tsujino , T. , Yasui , W. , Kameda , T. , Sano , T. , Nakayama , H. , Toge , T. and Tahara , E.Induction of growth factor‐receptor and metalloproteinase genes by epidermal growth factor and/or transforming growth factor‐α in human gastric carcinoma cell line MKN‐28 . Jpn. J. Cancer Res. , 81 , 793 – 798 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kuniyasu , H , Yoshida , K. , Yokozaki , H. , Yasui , W. , Ito , H. , Toge , T. , Ciardiello , F. , Persico , M. G. , Saeki , T. , Salomon , D. S. and Tahara , E.Expression of cripto, a novel gene of the epidermal growth factor family, in human gastrointestinal carcinomas . Jpn. J. Cancer Res. , 82 , 969 – 973 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ciardiello , F. , Kim , N , Saeki , T. , Dono , R. , Persico , M. G. , Plowman , G. D. , Garrigues , J. , Radke , S. , Todaro , G. J. and Salomon , D. S.Differential expression of epidermal growth factor‐related proteins in human colorectal tumors . Proc. Natl. Acad. Sci. USA , 88 , 7792 – 7796 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Saeki , T. , Stromberg , K. , Qi , C.‐F. , Gullick , W. J. , Tahara , E. , Normanno , N. , Ciardiello , F. , Kenney , N. , Johnson , G. R. and Salomon , D. S.Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors . Cancer Res. , 52 , 3467 – 3473 ( 1992. ). [PubMed] [Google Scholar]
  • 25.Cook , P. W. , Pittelkow , M. R. , Keeble W. W. , Graves‐Deal , R. , CoffeyR. J. , Jr. and Shipley , G. D.Amphiregulin messenger RNA is elevated in psoriatic epidermis and gastrointestinal carcinomas . Cancer Res. , 52 , 3224 – 3227 ( 1992. ). [PubMed] [Google Scholar]
  • 26.Tanimoto , H. , Yoshida , K. , Yokozaki , H. , Yasui , W. , Nakayama , H. , Ito , H. , Ohama , K. and Tahara , E.Expression of basic fibroblast growth factor in human gastric carcinomas . Virchows Arch. B , 61 , 263 – 267 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 27.Bugler , B. , Amalric , F. and Prats , H.Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor . Mol. Cell. Biol. , 11 , 573 – 577 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Bouche , G. , Gas , N. , Prats , H. , Baldin , V. , Tauber , J.‐P. , Teissie , J. and Amalric , F.Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing GCH‐G1 transition . Proc. Natl. Acad. Sci. USA , 84 , 6770 – 6774 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kitadai , Y. , Yasui , W. , Yokozaki , H. , Kuniyasu , H. , Haruma , K. , Kajiyama , G. and Tahara , E.The level of a transcription factor Spl is correlated with the expression of EGF receptor in human gastric carcinomas . Biochem. Biophys. Res. Commun. , 189 , 1342 – 1348 ( 1992. ). [DOI] [PubMed] [Google Scholar]

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