P38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma. (September 2016)

• Record Type: Journal Article
• Authors: Lin, Yuan; Mallen-St. Clair, Jon; Wang, Guanyu; Luo, Jie; Palma-Diaz, Fernando; Lai, Chi; Elashoff, David A.; Sharma, Sherven; Dubinett, Steven M.; St. John, Maie
• Is Part Of: Oral oncology. Volume 60(2016:Sep.)
• Page Start: 81
• Page End: 89
• Publication Date: 2016-09
• Subjects: EMT -- p38 -- p38IP -- Snail -- HNSCC; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2016.06.010
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: We document p38-dependent transcriptional regulation of E-cadherin in HNSCC. Inhibition of p38 results in an increase in E-cadherin and decreases Snail transcription and leads to a less invasive cellular phenotype. We demonstrate a reciprocal relationship between p38, p38IP and E-cadherin. Therapies targeting the p38-p38IP pathway may diminish the propensity for tumor metastasis by blocking the subsequent activation of EMT via Snail. Summary: Background: In the present study, we investigated the role of p38-p38IP signaling in the inflammation-induced promotion of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC). Methods: Quantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used. Results: p38 inhibitor treated and p38 shRNA HNSCC cell lines demonstrate a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of Snail. p38 binds to and stabilizes p38IP, a subunit of histone SPT3-TAF9-GCN5 acetyltransferase (STAGA), resulting in enhanced transcription of Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. In clinical HNSCC samples, p38 interacting protein (p38IP) is significantly increased compared to adjacent normal tissue. An inverse relationship between p38, p38IP and E-cadherin is demonstrated. Conclusions: Herein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC.