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Papilloma Development Is Delayed in Osteopontin-Null Mice: Implicating an Antiapoptosis Role for Osteopontin

Departments of ¹ Nutrition Sciences, ² Genetics, and ³ Dermatology and ⁴ Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama and ⁵ Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine

Requests for reprints: Pi-Ling Chang, Department of Nutrition Sciences, University of Alabama at Birmingham, 311 Susan Mott Webb Nutrition Sciences Building, 1675 University Boulevard, Birmingham, AL 35295-3360. Phone: 205-975-6624; Fax: 205-934-7049; E-mail: plchang{at}uab.edu.

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. (Cancer Res 2006; 66(14): 7119-27)

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