Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

Sophia Bornstein, Ruth White, Stephen Malkoski, Masako Oka, Gangwen Han, Timothy Cleaver, Douglas Reh, Peter Andersen, Neil Gross, Susan Olson, Chuxia Deng, Shi Long Lu, Xiao Jing Wang

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

Original languageEnglish (US)
Pages (from-to)3408-3419
Number of pages12
JournalJournal of Clinical Investigation
Volume119
Issue number11
DOIs
StatePublished - Nov 2 2009

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Genomic Instability
Head and Neck Neoplasms
Inflammation
Down-Regulation
Fanconi Anemia
Neck
Head
Smad4 Protein
Epithelium
Gene Knockout Techniques
Carcinoma, squamous cell of head and neck
Mouth Mucosa
DNA Repair
Neoplasms
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bornstein, S., White, R., Malkoski, S., Oka, M., Han, G., Cleaver, T., ... Wang, X. J. (2009). Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. Journal of Clinical Investigation, 119(11), 3408-3419. https://doi.org/10.1172/JCI38854

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. / Bornstein, Sophia; White, Ruth; Malkoski, Stephen; Oka, Masako; Han, Gangwen; Cleaver, Timothy; Reh, Douglas; Andersen, Peter; Gross, Neil; Olson, Susan; Deng, Chuxia; Lu, Shi Long; Wang, Xiao Jing.

In: Journal of Clinical Investigation, Vol. 119, No. 11, 02.11.2009, p. 3408-3419.

Research output: Contribution to journalArticle

Bornstein, S, White, R, Malkoski, S, Oka, M, Han, G, Cleaver, T, Reh, D, Andersen, P, Gross, N, Olson, S, Deng, C, Lu, SL & Wang, XJ 2009, 'Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation', Journal of Clinical Investigation, vol. 119, no. 11, pp. 3408-3419. https://doi.org/10.1172/JCI38854
Bornstein, Sophia ; White, Ruth ; Malkoski, Stephen ; Oka, Masako ; Han, Gangwen ; Cleaver, Timothy ; Reh, Douglas ; Andersen, Peter ; Gross, Neil ; Olson, Susan ; Deng, Chuxia ; Lu, Shi Long ; Wang, Xiao Jing. / Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 11. pp. 3408-3419.
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AU - Cleaver, Timothy

AU - Reh, Douglas

AU - Andersen, Peter

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