title: Myc-transformed epithelial cells down-regulate clusterin, which inhibits their growth in vitro and carcinogenesis in vivo.
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.
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6051, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
authors.forename: Isabelle
authors.initials: I
authors.lastname: Viard-Leveugle
authors.forename: Michael
authors.initials: M
authors.lastname: Dews
authors.forename: Philippe
authors.initials: P
authors.lastname: Wehrli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sevignani
authors.forename: Duonan
authors.initials: D
authors.lastname: Yu
authors.forename: Stacey
authors.initials: S
authors.lastname: Ricci
authors.forename: Wafik
authors.initials: W
authors.lastname: el-Deiry
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Gürkan
authors.initials: G
authors.lastname: Kaya
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D051152:Clusterin; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016259:Genes, myc / Q000502:physiology*; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D019700:Thrombospondin 1