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Altered cytokeratin expression and differentiation induction during neoplastic transformation of cultured rat liver cells by nickel subsulfide

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Abstract

Rat liver T51 B cells were maintained in the presence of low concentrations of Ni(H) derived from αNi3S2 for 3–I5 months in culture in order to monitor cytokeratin, differentiation, and transformation patterns. Nickel exposures caused irreversible, heritable juxtanuclear aggregates of cytokeratin CKSS, which increased in size and complexity with prolonged nickel exposure, eventually resembling Mallory bodies and expressing glutamyltransferase. Altered cytokeratin expression was accompanied by induction of differentiation, with markers of both bile ductular cells and hepatocytes, such as induction of cytokeratin polypeptides CK39 and CK49, cell morphology, and cytokeratin filament network changes, whereas control cultures similarly maintained for long periods in culture remained unchanged. Altered cytokeratin expression was also accompanied by acquisition of transformation markers—loss of density dependence, progression toward calcium independence, and (benign) growth in nude mice. Observed cytokeratin aberrations may be a factor in nickel carcinogenesis, in view of the known affinity of the metal for cellular structural proteins, especially keratin, which play a role in maintenance of cell behavior.

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Abbreviations

CK:

cytokeratin

GGT:

gamma-glutamyltransferase

HCM:

standard calcium medium

LCM:

low calcium medium (Ca2+ = 0.02 mM)

MB:

mallory body

NI:

neoplastic index (ratio of growth of cells in LCM/HCM)

Ni:

ni(II) used as leachate from αNi3S2

PBS:

phosphate-buffered saline

SB:

sodium butyrate

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Authors and Affiliations

  1. Drugs Directorate Health and Welfare, Canada, Ottawa, Canada

    S. H. H. Swierenga, R. Mueller & F. Lee

  2. Laval University Cancer Research Centre, Quebec, Quebec

    N. Marceau

  3. Kyoto Prefectural University, Kyoto, Japan

    Y. Katsuma

  4. Pathology Department, University of Ottawa, Ottawa, Canada

    S. W. French

Authors
  1. S. H. H. Swierenga
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  2. N. Marceau
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  3. Y. Katsuma
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  4. S. W. French
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  5. R. Mueller
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  6. F. Lee
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Swierenga, S.H.H., Marceau, N., Katsuma, Y. et al. Altered cytokeratin expression and differentiation induction during neoplastic transformation of cultured rat liver cells by nickel subsulfide. Cell Biol Toxicol 5, 271–286 (1989). https://doi.org/10.1007/BF01795356

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