Requirement of STAT3 Activation for Differentiation of Mucosal Stratified Squamous Epithelium
STAT3, a member of the signal transducers and activators of transcription (STAT) family, has been shown to play a key role in promoting proliferation, differentiation, or cell cycle progression, depending on cell type. A number of signaling pathways are altered in laryngeal papillomas, benign tumors induced by human papillomavirus 6/11. Papillomas overexpress the epidermal growth factor receptor and display enhanced MAP kinase and PI-3-kinase activity. They also show reduced activation of Akt and reduced levels of tyrosine-phosphorylated STAT3, due to overexpression of the tumor suppressor, PTEN. As papillomas show abnormalities in terminal differentiation, we examined the potential role of STAT3 in regulating epithelial differentiation. Laryngeal epithelial cells were suspended in supplemented serum-free medium. Differentiation was measured by Western blot analysis of keratin 13. Normal laryngeal epithelial cells were transfected with a constitutively active STAT3 or a dominant negative STAT3. Cells were transferred to suspension culture 24 h after transfection. Increased expression of keratin 13 was accompanied by the activation of STAT3 when differentiation was induced, and expression of a constitutively active STAT3 (STAT3C) enhanced the expression of keratin 13. In contrast, expression of a dominant negative STAT3 (Y705F) inhibited the expression of keratin 13. We conclude that activation of STAT3 is required for the differentiation of normal human stratified squamous epithelium.
This work was supported by grant P50DC00203 from the National Institute on Deafness and Other Communication Disorders and a Faculty Research Award from the North Shore-Long Island Jewish Research Institute.
We thank Dr Jennifer Grandis and Dr James Darnell who provided the dominant-negative STAT3 and the constitutively active STAT3. We express our gratitude to Dr Danile Besser who provided the STAT3 luciferase reporter and control constructs. Also, we thank Dr Allan Abramson and Dr Mark Shikowitz who provided normal and papilloma tissues, and May Nouri who provided normal laryngeal cell cultures.
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