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395 KERATINOCYTE-SPECIFIC SMAD2 ABLATION PROMOTES SKIN CARCINOGENESIS VIA AFFECTING GENES RELATED TO TUMOR INVASION AND ANGIOGENESIS.
  1. K. E. Hoot1,
  2. A. G. Li1,2,3,
  3. S. L. Lu1,2,3,
  4. G. W. Han1,2,3,
  5. W. Ju4,
  6. E. P. Bottinger4,
  7. X. J. Wang1,2,3
  1. 1Department of Cell and Developmental Biology
  2. 2Department of Dermatology
  3. 3Department of Otolaryngology, Oregon Health & Science University, Portland, OR
  4. 4Department of Medicine, Mount Sinai School of Medicine, New York, NY

Abstract

Purpose of Study Transforming growth factor β (TGF-β) has roles in both tumor suppression and promotion. Although Smad2 and Smad3 are TGF-β signaling mediators, their functions in mediating TGF-β signaling during cancer development remain to be determined. We have examined expression patterns of Smad2 and Smad3 in human skin SCCs and found that over 95% of tumor samples retain Smad3, whereas 70% of SCCs have lost the Smad2 protein. Previously, we have shown that Smad3 knockout mice are resistant to skin carcinogenesis due to abrogation of TGF-β-mediated tumor promotion effect.

Methods Used In the current study, we assessed the role of Smad2 in skin carcinogenesis by generating mice with keratinocyte-specific Smad2 deletion.

Summary of Results Although conditional Smad2 knockout mice did not develop spontaneous skin tumors, when exposed to a two-stage chemical carcinogenesis protocol, they exhibited accelerated tumor formation and malignant progression compared with wild-type mice. Smad2−/− tumors were more poorly differentiated in comparison with tumors from wild-type mice. At the papilloma stage, Smad2−/− tumors exhibited molecular alterations usually associated with late-stage SCC progression and epithelial-mesenchymal transition (EMT), eg, a significant elevation of keratin K8, snail, twist, tenascin C and vimentin. Additionally, Smad2−/− tumors displayed HGF-dependent vessel growth culminating in approximately three times the angiogenesis seen in Smad2+/+ tumors. Since these molecules are documented or potential TGF-β target genes, we examined TGF-β1 levels in Smad2−/− tumors. We found that neither the TGF-β1 level nor Smad3 activation was elevated in Smad2−/− tumors.

Conclusions Reached Thus, our study suggests that Smad2 loss results in the elevation of tumor invasion-associated and angiogenesis genes via a TGF-β-independent mechanism.

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