Journal Article

Genetic ablation of cyclooxygenase-2 in keratinocytes produces a cell-autonomous defect in tumor formation

Huei-Chen Lao, Jacqueline K. Akunda, Kyung-Soo Chun, Gordon P. Flake, Stuart H. Yuspa and Robert Langenbach

in Carcinogenesis

Volume 33, issue 11, pages 2293-2300
Published in print November 2012 | ISSN: 0143-3334
Published online August 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs267
Genetic ablation of cyclooxygenase-2 in keratinocytes produces a cell-autonomous defect in tumor formation

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Using a mouse skin tumor model, we reported previously that cyclooxygenase-2 (COX-2) deficiency reduced papilloma formation. However, this model did not differentiate between the effects of systemic COX-2-deficiency and keratinocyte-specific COX-2 deficiency on tumor formation. To determine whether keratinocyte-specific COX-2 deficiency reduced papilloma formation, v-H-ras-transformed COX-2+/+ and COX-2−/− keratinocytes were grafted onto nude mice and tumor development was compared. Transformed COX-2+/+ and COX-2−/− keratinocytes expressed similar levels of H-ras, epidermal growth factor receptor and phospho-extracellular signal-regulated kinase1/2 in vitro; and COX-2-deficiency did not reduce uninfected or v-H-ras infected keratinocyte replication. In contrast, tumors arising from grafted transformed COX-2+/+ and COX-2−/− keratinocytes expressed similar levels of H-ras, but COX-2 deficiency reduced phospho-extracellular signal-regulated kinase 1/2 and epidermal growth factor receptor levels 50–60% and tumor volume by 80% at 3 weeks. Two factors appeared to account for the reduced papilloma size. First, papillomas derived from COX-2−/− keratinocytes showed about 70% decreased proliferation, as measured by bromodeoxyuridine incorporation, compared with papillomas derived from COX-2+/+ keratinocytes. Second, keratin 1 immunostaining of papillomas indicated that COX-2−/− keratinocytes prematurely initiated terminal differentiation. Differences in the levels of apoptosis and vascularization did not appear to be contributing factors as their levels were similar in tumors derived from COX-2−/− and COX-2+/+ keratinocytes. Overall, the data are in agreement with our previous observations that decreased papilloma number and size on COX-2−/− mice resulted from reduced keratinocyte proliferation and accelerated keratinocyte differentiation. Furthermore, the data indicate that deficiency/inhibition of COX-2 in the initiated keratinocyte is an important determinant of papilloma forming ability.

Journal Article.  6339 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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