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Myc-transformed epithelial cells down-regulate clusterin, which inhibits their growth in vitro and carcinogenesis in vivo.
- Source :
-
Cancer research [Cancer Res] 2004 May 01; Vol. 64 (9), pp. 3126-36. - Publication Year :
- 2004
-
Abstract
- Effective treatment of malignant carcinomas requires identification of proteins regulating epithelial cell proliferation. To this end, we compared gene expression profiles in murine colonocytes and their c-Myc-transformed counterparts, which possess enhanced proliferative potential. A surprisingly short list of deregulated genes included the cDNA for clusterin, an extracellular glycoprotein without a firmly established function. We had previously demonstrated that in organs such as skin, clusterin expression is restricted to differentiating but not proliferating cell layers, suggesting a possible negative role in cell division. Indeed, its transient overexpression in Myc-transduced colonocytes decreased cell accumulation. Furthermore, clusterin was down-regulated in rapidly dividing human keratinocytes infected with a Myc-encoding adenovirus. Its knockdown via antisense RNA in neoplastic epidermoid cells enhanced proliferation. Finally, recombinant human clusterin suppressed, in a dose-dependent manner, DNA replication in keratinocytes and other cells of epithelial origin. Thus, clusterin appears to be an inhibitor of epithelial cell proliferation in vitro. To determine whether it also affects neoplastic growth in vivo, we compared wild-type and clusterin-null mice with respect to their sensitivity to 7, 12-dimethylbenz(a)anthracene /12-Otetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis. We observed that the mean number of papillomas/mouse was higher in clusterin-null animals. Moreover, these papillomas did not regress as readily as in wild-type mice and persisted beyond week 35. The rate of progression toward squamous cell carcinoma was not altered, although those developing in clusterin-null mice were on average better differentiated. These data suggest that clusterin not only suppresses epithelial cell proliferation in vitro but also interferes with the promotion stage of skin carcinogenesis.
- Subjects :
- Animals
Cell Division drug effects
Cell Division physiology
Cell Transformation, Neoplastic
Clusterin
Down-Regulation
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells physiology
Glycoproteins biosynthesis
Glycoproteins genetics
Glycoproteins pharmacology
Humans
Keratinocytes drug effects
Keratinocytes physiology
Mice
Mice, Knockout
Molecular Chaperones biosynthesis
Molecular Chaperones genetics
Molecular Chaperones pharmacology
Recombinant Proteins pharmacology
Skin Neoplasms genetics
Skin Neoplasms prevention & control
Thrombospondin 1 antagonists & inhibitors
Thrombospondin 1 biosynthesis
Thrombospondin 1 genetics
Genes, myc physiology
Glycoproteins physiology
Keratinocytes cytology
Keratinocytes metabolism
Molecular Chaperones physiology
Skin Neoplasms metabolism
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 64
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 15126350
- Full Text :
- https://doi.org/10.1158/0008-5472.can-03-1953