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. 2000 Oct;91(10):979–986. doi: 10.1111/j.1349-7006.2000.tb00874.x

Overexpression of Midkine in Pancreatic Duct Adenocarcinomas Induced by N‐Nitrosobis(2‐oxopropyl)amine in Hamsters and Their Cell Lines

Masahiro Tsutsumi 1,✉, Kenji Kadomatsu 2, Toshifumi Tsujiuchi 1, Hiroyuki Sakitani 1, Shinya Ikematsu 3, Tadahiko Kubozoe 1, Masatoshi Yoshimoto 1, Takashi Muramatsu 2, Sadatoshi Sakuma 3, Yoichi Konishi 1
PMCID: PMC5926258  PMID: 11050467

Abstract

The expression of midkine (MK) was investigated in pancreatic ductal hyperplasias, atypical hyperplasias and adenocarcinomas induced by N‐nitrosobis(2‐oxopropyl)amine (BOP) in hamsters, and in hamster ductal adenocarcinoma cell lines (HPD‐1NR, ‐2NR and ‐3NR). MK mRNA was clearly overexpressed in invasive pancreatic duct adenocarcinomas (PCs) and the three cell lines as assessed by northern blot analysis, and MK protein expression increased from ductal hyperplasia through atypical hyperplasias, intraductal carcinomas and invasive PCs by immunohistochemistry. The extent of overexpression of MK mRNA in PCs was almost the same as in hamster whole embryonic tissue. MK is reported to be a retinoid‐responsive gene, but MK mRNA expression was not affected by treatment with all‐trans retinoic acid (tRA) or N‐(4‐hydroxyphenyl)retinamide (4‐ HPR) in HPD‐1NR cells. The results thus suggest that MK expression is involved in the development and progression of pancreatic ductal adenocarcinomas induced by BOP in hamsters, with loss of upregulation by retinoic acid.

Keywords: Midkine, Pancreatic duct carcinogenesis, Hamster, 4‐HPR, tRA

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REFERENCES

  • 1. ) Wingo , P. A. , Ries , L. A. , Giovino , G. A. , Miller , D. S. , Rosenberg , H. M. , Shopland , D. R. , Thun , M. J. and Edwards , B. K.Annual report to the nation on the status of cancer, 1973–1996 . J. Natl. Cancer Inst. , 91 , 675 – 690 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Health and Welfare Statistics in Japan . Main causes of death in Japan . J. Health Welfare Stat. , 43 , 52 – 60 ( 1996. ) ( in Japanese ). [Google Scholar]
  • 3. ) Pour , P. M. , Kruger , F. W. , Althoff , J. , Cardesa , A. and Mohr , U.Cancer of the pancreas induced in the Syrian golden hamster . Am. J. Pathol. , 76 , 349 – 358 ( 1974. ). [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Pour , P. M. , Salmasi , S. Z. and Runge , R. G.Selective induction of pancreatic ductular tumors by single dose of N‐nitrosobis(2‐oxopropyl)amine in Syrian golden hamsters . Cancer Lett. , 4 , 317 – 323 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Pour , P. M. , Runge , R. G. , Birt , D. , Gingell , R. , Lawson , T. , Nageal , D. and Wallcave , L.Current knowledge of pancreatic carcinogenesis in the hamster and its relation to the human disease . Cancer , 47 , 1573 – 1589 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Mizumoto , K. , Tsutsumi , M. , Denda , A. and Konishi , Y.Rapid production of pancreatic carcinoma by initiation with N‐nitrosobis(2‐oxopropyl)amine and repeated augmentation pressure in hamsters . J. Natl. Cancer Inst. , 80 , 1564 – 1567 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Mizumoto , K. , Kitazawa , S. , Ito , S. , Takashima , Y. , Tsutsumi , M. , Denda , A. and Konishi , Y.Cycles of repeated augmentation pressure in rapid production of pancreatic and cholangiocelluar carcinomas in hamsters initiated with N‐nitrosobis(2‐oxopropyl)amine . Carcinogenesis , 10 , 1457 – 1459 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Mizumoto , K. , Tsutsumi , M. , Kitazawa , S. , Denda , A. and Konishi , Y.Usefulness of a rapid production model for pancreatic carcinoma in male hamsters . Cancer Lett. , 49 , 211 – 215 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Solt , D. and Farber , E.New principle for the analysis of chemical carcinogenesis . Nature , 263 , 701 – 703 ( 1976. ). [Google Scholar]
  • 10. ) Pitot , H. C. , Barsness , L. and Goldworthy , T.Biochemical characterization of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine . Nature , 271 , 456 – 458 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Mori , T. , Tsutsumi , M. , Noguchi , O. , Horiguchi , K. , Honoki , K. , Okita , S. , Suzuki , F. and Konishi , Y.Characterization of three cloned cell lines from a N‐nitrosobis(2‐ hydroxypropyl)amine‐induced transplantable hamster pancreatic ductal adenocarcinoma . Int. J. Pancreatol. , 16 , 171 – 177 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Konishi , Y. , Tsutsumi , M. and Tsujiuchi , T.Mechanistic analysis of pancreatic ductal carcinogenesis in hamsters . Pancreas , 16 , 300 – 306 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Egawa , S. , Tsutsumi , M. , Konishi , Y. , Kobari , M. , Matsuno , S. , Nagasaki , K. , Futami , H. and Yamaguchi , K.The role of angiogenesis in the tumor growth of Syrian hamster pancreatic cancer cell line HPD‐NR . Gastroenterology , 108 , 1526 – 1533 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Kadomatsu , K. , Tomomura , M. and Muramatsu , T.cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cell and in midgestation period of mouse embryogenesis . Biochem. Biophys. Res. Commun. , 151 , 1312 – 1328 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Tomomura , M. , Kadomatsu , K. , Matsubara , S. and Muramatsu , T.A retinoic acid‐responsive gene, MK, found in the teratocarcinoma system. Heterogeneity of the transcript and the nature of the translation product . J. Biol. Chem. , 265 , 10765 – 10770 ( 1990. ). [PubMed] [Google Scholar]
  • 16. ) Kadomatsu , K. , Huang , R.‐P. , Suganuma , T. , Murata , F. and Muramatsu , T.A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in a spatially and temporally controlled manner during mouse embryogenesis . J. Cell Biol. , 110 , 607 – 616 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Mitsiadis , T. A. , Salmivirta , M. , Muramatsu , T. , Muramatsu , H. , Rauvala , H. , Lehtonen , E. , Jalkanen , M. and Thesleff , I.Expression of the heparin‐binding cytokines, midkine (MK) and HB‐GAM (pleiotrophin) is associated with epithelial‐mesenchymal interactions during fetal development and organogenesis . Development , 121 , 37 – 51 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Mitsiadis , T. A. , Muramatsu , T. , Muramatsu , H. and Thesleff , I.Midkine (MK), a heparin‐binding growth/differentiation factor, is regulated by retinoic and epithelialmesenchymal interactions in the developing mouse tooth, and affects cell proliferation and morphogenesis . J. Cell Biol. , 129 , 267 – 281 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Muramatsu , H. and Muramatsu , T.Purification of recombinant midkine and examination of its biological activities: functional comparison of new heparin binding factors . Biochem. Biophys. Res. Commun. , 177 , 652 – 658 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Michikawa , M. , Kikuchi , S. , Muramatsu , H. , Muramatsu , T. and Kim , S. U.Retinoic acid responsive gene product, midkine, has neurotrophic functions for mouse spinal cord and dorsal root ganglion neurons in culture . J. Neurosci. Res. , 35 , 530 – 539 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Kojima , S. , Muramatsu , H. , Amanuma , H. and Muramatsu , T.Midkine is a heat and acid stable polypeptide capable of enhancing plasminogen activator activity and neurite outgrowth extension . J. Biol. Chem. , 270 , 9590 – 9596 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Tsutsui , J. , Kadomatsu , K. , Matsubara , S. , Nakagawara , A. , Hamanoue , M. , Takao , S. , Shimazu , H. , Ohi , Y. and Muramatsu , T.A new family of heparin‐binding growth/differentiation factors: increased midkine expression in Wilms' tumor and other human carcinomas . Cancer Res. , 53 , 1281 – 1285 ( 1993. ). [PubMed] [Google Scholar]
  • 23. ) Aridome , K. , Tsutsui , J. , Takao , S. , Kadomatsu , K. , Ozawa , M. , Aikou , K. and Muramatsu , T.Increased midkine gene expression in human gastrointestinal cancers . Jpn. J. Cancer Res. , 86 , 655 – 661 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Nakagawara , A. , Milbrandt , J. , Muramatsu , T. , Deuel , T. , Zhao , H. , Cnaan , A. and Brodeuri , G.Differential expression of pleiotrophin and midkine in advanced neuroblastomas . Cancer Res. , 55 , 1792 – 1797 ( 1995. ). [PubMed] [Google Scholar]
  • 25. ) Garver , R. I. , Jr. , Radford , D. M. , Donis‐Keller , H. , Wick , M. R. and Milner , P. G.Midkine and pleiotrophin expression in normal and malignant breast tissue . Cancer , 74 , 1584 – 1590 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Garver , R. I.Jr. , Chan , C. S. and Milner , P. G.Reciprocal expression of pleiotrophin and midkine in normal versus malignant lung tissues . Am. J. Respir. Cell Mol. Biol. , 9 , 463 – 466 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Mishima , K. , Asai , A. , Kadomatsu , K. , Ino , Y. , Nomura , K. , Narita , Y. , Muramatsu , T. and Kirino , T.Increased expression of midkine during the progression of human astrocytomas . Neurosci. Lett. , 233 , 29 – 32 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) O'Brien , D. , Cranston , D. , Fuggle , S. , Bicknell , R. and Harris , A. L.The angiogenic factor midkine is expressed in bladder cancer, and overexpression correlates with a poor outcome in patients with invasive cancers . Cancer Res. , 56 , 2515 – 2518 ( 1996. ). [PubMed] [Google Scholar]
  • 29. ) Sakitani , H. , Tsutsumi , M. , Kadomatsu , K. , Ikematsu , M. , Takahama , M. , Iki , K. , Tsujiuchi , T. , Muramatsu , T. , Sakuma , S. , Sakaki , T. and Konishi , Y.Overexpression of midkine in lung tumors induced by N‐nitrosobis(2‐hydroxypropyl) amine in rats and its increase with progression . Carcinogenesis , 20 , 465 – 469 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Chen , Y. , Mckenzie , K. E. , Aldaz , C. M. and Sukumar , S.Midkine in the progression of rat N‐nitroso‐N‐methylureainduced mammary tumors . Mol. Carcinog. , 17 , 112 – 116 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Cathala , G. , Savouret , J. F. and Mandez , B.Laboratory methods: a method for isolation of intact, transcriptionally active ribonucleotic acid . DNA , 2 , 329 – 335 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Franzier , M. L. , Mars , W. , Florine , D. L. , Montagna , R. A. and Saunders , G. F.Efficient extraction of RNA from mammalian tissue . Mol. Cell. Biochem. , 56 , 113 – 122 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Korc , M. , Chandrasekar , B. , Yamanaka , Y. , Freiss , H. , Buchier , M. and Beger , H. G.Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concominant increase in the levels of epidermal growth factor and transforming growth factor alpha . J. Clin. Invest. , 90 , 1352 – 1360 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. ) Smith , J. J. , Derynck , R. and Korc , M.Production of transforming growth factor α in human pancreatic cancer cells: evidence for a superagonist autocrine cycle . Proc. Natl. Acad. Sci. USA , 84 , 7567 – 7570 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. ) Bergmann , U. , Funatomi , M. , Yokoyama , M. , Beger , H. G. and Korc , M.Insulin‐like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles . Cancer Res. , 55 , 2007 – 2011 ( 1995. ). [PubMed] [Google Scholar]
  • 36. ) Ebert , M. , Yokoyama , M. , Freiss , H. , Buchier , M. W. and Korc , M.Coexpression of the c‐met proto‐oncogene and hepatocyte growth factor in human pancreatic cancer . Cancer Res. , 54 , 5775 – 5778 ( 1994. ). [PubMed] [Google Scholar]
  • 37. ) DiRenzo , M. F. , Poulsom , R. , Olivero , M. , Comoglio , P. M. and Lemoine , N. R.Expression of the met/hepatocyte growth factor receptor in human pancreatic cancer . Cancer Res. , 55 , 1129 – 1138 ( 1995. ). [PubMed] [Google Scholar]
  • 38. ) Ratovitski , E. A. , Kotzbauer , P. T. , Milbrandt , J. , Lowenstein , C. J. and Burrow , C. R.Midkine induces tumor cell proliferation and binds to a high affinity signaling receptor associated with JAK tyrosine kinases . J. Biol. Chem. , 273 , 3654 – 3660 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 39. ) Maeda , N. , Ichihara‐Tanaka , K. , Kimura , T. , Kadomatsu , K. , Muramatsu , T. and Noda , M.A receptor‐like proteintyrosine phosphatase PTPζ/RPTPβ binds a heparin‐binding growth factor midkine . J. Biol. Chem. , 274 , 12474 – 12479 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) Owada , K. , Sanjo , N. , Kobayashi , T. , Mizusawa , H. , Muramatsu , H. , Muramatsu , T. and Michikawa , M.Midkine inhibits caspase‐dependent apoptosis via the activation of mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase in cultured neurons . J. Neurochem. , 73 , 2084 – 2092 ( 1999. ). [PubMed] [Google Scholar]
  • 41. ) Kadomatsu , K. , Hagihara , M. , Akhter , S. , Fan , Q. W. , Muramatsu , H. and Muramatsu , T.Midkine induces the transformation of NIH3T3 cells . Br. J. Cancer , 75 , 354 – 359 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. ) Horiba , M. , Kadomatsu , K. , Nakamura , E. , Muramatsu , H. , Ikematsu , S. , Sakuma , S. , Hayashi , K. , Yuzawa , Y. , Matsuo , S. , Kuzuya , M. , Kname , T. , Hirai , M. , Saito , H. and Muramatsu , T.Neointima formation in a restenosis model is suppressed in midkine‐deficient mice . J. Clin. Invest. , 105 , 485 – 495 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. ) Qi , M. , Ikematsu , S. , Ichihara‐Tanaka , K. , Sakuma , S. , Muramatsu , T. and Kadomatsu , K.Midkine rescues Wilms tumor cells from cisplatin‐induced apoptosis: regulation of bcl‐2 expression by midkine . J. Biochem. , 127 , 269 – 277 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 44. ) Smith , M. A. , Parkinson , D. R. , Cheson , B. D. and Friedman , M. A.Retinoids in cancer therapy . J. Clin. Oncol. , 10 , 839 – 864 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 45. ) Matsubara , S. , Take , M. , Pedraza , C. and Muramatsu , T.Mapping and characterization of a retinoic acid‐responsive enhancer of midkine, a novel heparin‐binding growth/differentiation factor with neurotrophic activity . J. Biochem. , 115 , 1088 – 1096 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 46. ) Bunk , M. J. , Kinahan , J. J. and Sarkar , N. H.Biotransformation and protein binding of N‐(4‐hydroxyphenyl)retinamide in murine mammary epithelial cells . Cancer Lett. , 26 , 319 – 326 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 47. ) Majima , T. , Tsutsumi , M. , Nishino , H. , Tsunoda , T. and Konishi , Y.Inhibitory effects of β‐carotene, palm carotene, and green tea polyphenols on pancreatic carcinogenesis initiated by N‐nitrosobis(2‐oxopropyl)amine in Syrian golden hamsters . Pancreas , 16 , 13 – 18 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 48. ) Folkman , J. , Watson , K. , Ingber , D. and Hanahan , D.Induction of angiogenesis during the transition from hyperplasia to neoplasia . Nature , 339 , 58 – 61 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 49. ) Choudhuri , R. , Zhang , H. T. , Donnini , S. , Ziche , M. and Bicknell , R.An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis . Cancer Res. , 37 , 1814 – 1819 ( 1997. ). [PubMed] [Google Scholar]
  • 50. ) Ikeda , N. , Adachi , M. and Taki , T.Prognostic significance of angiogenesis in human pancreatic cancer . Br. J. Cancer , 79 , 1553 – 1563 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. ) Ikematsu , S. , Yano , A. , Aridome , K. , Kikuchi , M. , Kumai , H. , Nagano , H. , Okamoto , K. , Oda , M. , Sakuma , S. , Aikou , T. , Muramatsu , H. , Kadomatsu , K. and Muramatsu , T.Serum midkine levels are increased in patients with various types of carcinomas . Br. J. Cancer , in press . [DOI] [PMC free article] [PubMed]

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