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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1996 May;87(5):505–511. doi: 10.1111/j.1349-7006.1996.tb00252.x

Effect of MUC1 Mucin, an Anti‐adhesion Molecule, on Tumor Cell Growth

Yusuke Makiguchi 1, Yuji Hinoda 1,, Kohzoh Imai 1
PMCID: PMC5921124  PMID: 8641988

Abstract

MUC1 mucin is expressed in a wide variety of tumors and is considered to function as an anti‐adhesion molecule which inhibits cell‐to‐cell interactions. To reveal the biological significance of this activity in tumor cells, MUC1 cDNA was transfected into EJNIH3T3 cells and human colon cancer cell lines, CHCY1 and DLD1. The in vivo growth rate of MUC1+ (MUC1‐transfected) EJNIH3T3, CHCY1 and DLD1 cells in SCID mice was clearly lower than that of MUC1 (mock transfectant) cells. Several in vitro experiments using MUC1+ EJNIH3T3 cells were performed to analyze the mechanisms for the decreased in vivo tumor growth. It was found that (i) the in vitro growth rate of MUC1+ EJNIH3T3 cells was also decreased compared to that of MUC1 cells, (ii) the DNA synthesis of MUC1+ EJNIH3T3 cells after stimulation with either growth factor (fetal calf serum or bombesin) or extracellular matrix (collagen or fibronectin) was lower than that of MUC1 cells, and (iii) MUC1+ EJNIH3T3 cells grew more slowly than MUC1 cells on both collagen‐ and fibronectin‐coated dishes. These data suggest that MUC1 mucin may regulate tumor cell growth through inhibition of cell‐to‐cell, growth factor‐to‐receptor and cell‐to‐matrix interactions.

Keywords: MUC1 gene, Mucin, Anti‐adhesion activity, Tumor cell growth, Growth regulation

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REFERENCES

  • 1. ) Lightenberg , M. J. L. , Vos , H. L. , Gennissen , A. M. C. and Hilkens , J.Episialin, a carcinoma‐associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini . J. Biol. Chem. , 265 , 5573 – 5578 ( 1990. ). [PubMed] [Google Scholar]
  • 2. ) Wreshner , D. H. , Hareuveni , M. , Tsarfaty , I. , Smorodinsky , N. , Horev , J. , Zaretsky , J. , Kotkes , P. , Weiss , M. , Lathe , R. , Dion , A. and Keydar , I.Human epithelial tumor antigen cDNA sequences. Differential splicing may generate multiple protein forms . Eur. J. Biochem. , 189 , 463 – 473 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Gendler , S. J. , Lancaster , C. A. , Taylor‐Papadimitriou , J. , Duhig , T. , Peat , N. , Burchell , J. , Lalani , E.‐N. and Wilson , D.Molecular cloning and expression of human tumor‐associated polymorphic epithelial mucin . J. Biol. Chem. , 265 , 15286 – 15293 ( 1990. ). [PubMed] [Google Scholar]
  • 4. ) Lan , M. S. , Batra , S. K. , Qui , W.‐N. , Metzger , R. S. and Hollingsworth , M. A.Cloning and sequencing of a human pancreatic mucin cDNA . J. Biol. Chem. , 265 , 15294 – 15299 ( 1990. ). [PubMed] [Google Scholar]
  • 5. ) Gum , J. R.Mucin genes and the proteins they encode: structure, diversity, and regulation . Am. J. Respr. Cell. Mol. Biol. , 7 , 557 – 564 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Nishimori , I. , Perini , F. , Mountjoy , K. P. , Sanderson , S. D. , Johnson , N. , Cerny , R. L. , Gross , M. L. , Darell Fontenot , J. and Hollingsworth , M. A.N‐Acetylgalactosamine glycosylation of MUC1 tandem repeat peptides by pancreatic tumor cell extracts . Cancer Res. , 54 , 3738 – 3744 ( 1994. ). [PubMed] [Google Scholar]
  • 7. ) Ho , S. B. , Niehaus , G. A. , Lyftogt , C. , Yan , P. S. , Cherwitz , D. L. , Gum , E. T. , Dahiya , R. and Kim , Y. S.Heterogeneity of mucin gene expression in normal and neoplastic tissues . Cancer Res. , 53 , 641 – 651 ( 1993. ). [PubMed] [Google Scholar]
  • 8. ) Lightenberg , M. J. L. , Buijs , F. , Vos , H. L. and Hilkens , J.Suppression of cellular aggregation by high level of episialin . Cancer Res. , 52 , 2318 – 2324 ( 1992. ). [PubMed] [Google Scholar]
  • 9. ) van de Wiel‐van Kemenade , E. , Lightenberg , M. J. L. , de Boer , A. J. , Buijs , F. , Vos , H. L. , Melief , C. J. M. , Hilkens , J. and Figdor , C. G.Episialin (MUC1) inhibits cytotoxic lymphocyte‐target cell interaction . J. Immunol. , 151 , 767 – 776 ( 1993. ). [PubMed] [Google Scholar]
  • 10. ) Ban , T. , Imai , K. and Yachi , A.Immunohistological and immunochemical characterization of a novel pancreatic cancer‐associated antigen MUSE11 . Cancer Res. , 49 , 7141 – 7146 ( 1989. ). [PubMed] [Google Scholar]
  • 11. ) Hinoda , Y. , Nakagawa , N. , Ohe , Y. , Kakiuchi , H. , Tsujisaki , M. , Imai , K. and Yachi , A.Recognition of the polypeptide core of mucin by monoclonal antibody MUSE11 against an adenocarcinoma‐associated antigen . Jpn. J. Cancer Res. , 81 , 1206 – 1209 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Rojas , M. , Fuks , A. and Stanners , C. P.Biliary glycoprotein, a member of the immunoglobulin supergene family, functions in vitro as a Ca2+‐dependent intercellular adhesion molecule . Cell Growth Differ. , 1 , 527 – 533 ( 1990. ). [PubMed] [Google Scholar]
  • 13. ) Kuan , S. F. , Byrd , J. C. , Basbaum , C. B. and Kim , Y. S.Inhibition of mucin glycosylation by aryl‐N‐acetyl‐α‐galactosaminides in human colon cancer cells . J. Biol. Chem. , 264 , 19271 – 19277 ( 1989. ). [PubMed] [Google Scholar]
  • 14. ) Ikeda , H. , Kanakura , Y. , Takami , T. , Kuriu , A. , Kitayama , H. , Ishikawa , J. , Kanayama , Y. , Yonezawa , T. , Tarui , S. and Griffin , J. D.Expression and functional role of the proto‐oncogene c‐kit in acute myeloblastic leukemia for stem cell factor . Blood , 78 , 2962 – 2968 ( 1991. ). [PubMed] [Google Scholar]
  • 15. ) Cai , H. , Szeberenyi , J. and Cooper , G. M.Effect of a dominant inhibitory Ha‐ras mutation on mitogenic signal transduction in NIH3T3 cells . Mol. Cell. Biol. , 10 , 5314 – 5323 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Woll , P. J. and Rozengurt , E.Bombesin and bombesin antagonists: studies in Swiss 3T3 cells and human small cell lung cancer . Br. J. Cancer , 57 , 579 – 586 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Vleminckx , K. , Vakaet , L. , Jr. , Mareel , M. , Fiers , W. and van Roy , F.Genetic manipulation of E‐cadherin expression by epithelial tumor cells reveals an invasion suppressor role . Cell , 66 , 107 – 119 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Schipper , J. H. , Frixen , U. H. , Behrens , J. , Unger , A. , Jahnke , K. and Birchmeier , W.E‐cadherin expression in squamous cell carcinomas of head and neck: inverse correlation with tumor dedifferentiation and lymph node metastasis . Cancer Res. , 51 , 6328 – 6337 ( 1991. ). [PubMed] [Google Scholar]
  • 19. ) Stallmach , A. , Lampe , B. V. , Orzechowski , H.‐D. , Matthes , H. and Ricken , E.‐O.Increased fibronectin‐receptor expression in colon carcinoma‐derived HT29 cells decreases tumorigenicity in nude mice . Gastroenterology , 106 , 19 – 27 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Zachary , I. , Sinnett‐Smith , J. and Rozengurt , E.Bombesin, vasopressin, and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells . J. Biol. Chem. , 267 , 19031 – 19034 ( 1992. ). [PubMed] [Google Scholar]
  • 21. ) Ruoslahti , E. and Yamaguchi , Y.Proteoglycans as modulators of growth factor activities . Cell , 64 , 867 – 869 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Yayon , A. , Klagsbrun , M. , Esko , J. D. , Leder , P. and Ornitz , D. M.Cell surface, heparin‐like molecules are required for binding of fibroblast growth factor to its high affinity receptor . Cell , 64 , 841 – 848 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Roberts , R. , Gallagher , J. , Spooncer , E. , Allen , T. D. , Bloomfield , F. and Dexter , T. M.Heparan sulfate bound growth factors: a mechanism for stromal cell mediated hematopoiesis . Nature , 332 , 376 – 378 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Li , Y.‐S. , Milner , P. G. , Chauhan , A. K. , Watson , M. A. , Hoffman , R. M. , Kodner , C. M. , Milbrandt , J. and Deuel , T. F.Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity . Science , 250 , 1690 – 1694 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Yamaguchi , Y. , Mann , D. M. and Ruoslahti , E.Negative regulation of transforming growth factor‐β by the proteoglycan decorin . Nature , 346 , 281 – 284 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Batra , S. K. , Lern , H. F. , Worlock , A. J. , Metzgar , R. S. and Hollingsworth , M. A.Transfection of the human MUC1 mucin gene into a poorly differentiated human pancreatic tumor cell line, Panc1: integration, expression and ultrastructural changes . J. Cell Sci. , 100 , 841 – 849 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Yamagata , M. , Suzuki , S. , Akiyama , S. K. , Yamada , K. M. and Kimata , K.Regulation of cell‐substrate adhesion by proteoglycans immobilized on extracellular substances . J. Biol. Chem. , 264 , 8012 – 8018 ( 1989. ). [PubMed] [Google Scholar]
  • 28. ) Chiquet‐Ehrismann , R. , Kalla , P. , Person , C. A. , Beck , K. and Chiquet , M.Tenascin interferes with fibronectin action . Cell , 53 , 383 – 390 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Stallmach , A. , Lampe , B. V. , Mattehes , G. , Bornhoft , G. and Riecken , E. O.Differential loss of integrin adhesion molecules on human colonic epithelial cells during the benign to malignant tumor transformation . Gut , 33 , 342 – 346 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Guan , J. and Shalloway , D.Regulation of focal adhesion associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation . Nature , 358 , 690 – 692 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Chen , Q. , Kinch , M. S. , Lin , T. H. , Burridge , K. and Juliano , R. L.Integrin mediated cell adhesion activates mitogen‐activated protein kinases . J. Biol. Chem. , 269 , 26602 – 26605 ( 1994. ). [PubMed] [Google Scholar]
  • 32. ) Jentoft , N.Why are proteins O‐glycosylated ? Trends Biochem. Sci. , 15 , 291 – 294 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Hilkens , J. , Lightenberg , M. J. L. , Vos , H. L. and Litvinov , S. V.Cell membrane‐associated mucins and their adhesion‐modulating property . Trends Biochem. Sci. , 17 , 359 – 363 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Nakamori , S. , Ota , D. M. , Cleary , K. R. , Shirotani , K. and Irimura , T.MUC1 mucin expression as a marker of progression and metastasis of human colorectal carcinoma . Gastroenterology , 106 , 353 – 361 ( 1994. ). [DOI] [PubMed] [Google Scholar]

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