title: Papilloma development is delayed in osteopontin-null mice: implicating an antiapoptosis role for osteopontin.
abstract: Osteopontin is a secreted, adhesive glycoprotein, whose expression is markedly elevated in several types of cancer and premalignant lesions, implicating its association with carcinogenesis. To test the hypothesis that induced osteopontin is involved in tumor promotion in vivo, osteopontin-null and wild-type (WT) mice were subjected to a two-stage skin chemical carcinogenesis protocol. Mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) applied on to the dorsal skin followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 27 weeks. Osteopontin-null mice showed a marked decrease both in tumor/papilloma incidence and multiplicity compared with WT mice. Osteopontin is minimally expressed in normal epidermis, but on treatment with TPA its expression is highly induced. To determine the possible mechanism(s) by which osteopontin regulates tumor development, we examined cell proliferation and cell survival. Epidermis from osteopontin-null and WT mice treated with TPA thrice or with DMBA followed by TPA for 11 weeks showed a similar increase in epidermal hyperplasia, suggesting that osteopontin does not mediate TPA-induced cell proliferation. Bromodeoxyuridine staining of papillomas and adjacent epidermis showed no difference in cell proliferation between groups. However, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analyses indicated a greater number of apoptotic cells in DMBA-treated skin and papillomas from osteopontin-null versus WT mice. These studies are the first to show that induction of the matricellular protein osteopontin facilitates DMBA/TPA-induced cutaneous carcinogenesis most likely through prevention of apoptosis.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35295-3360, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hsieh
authors.forename: M Margaret
authors.initials: MM
authors.lastname: Juliana
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Hicks
authors.forename: Gong
authors.initials: G
authors.lastname: Feng
authors.forename: Craig
authors.initials: C
authors.lastname: Elmets
authors.forename: Lucy
authors.initials: L
authors.lastname: Liaw
authors.forename: Pi-Ling
authors.initials: PL
authors.lastname: Chang
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002273:Carcinogens; D048708:Cell Growth Processes / Q000502:physiology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D053495:Osteopontin; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000172:deficiency*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D002273:Carcinogens; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate