Identification of a novel proto-oncogenic network in head and neck squamous cell carcinoma

Smitha Rose Georgy, Michael Cangkrama, Seema Srivastava, Darren Partridge, Alana Auden, Sebastian Dworkin, Catriona Ann McLean, Stephen Marsden Jane, Charbel Darido

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20 Citations (Scopus)

Abstract

Background: The developmental transcription factor Grainyhead-like 3 (GRHL3) plays a critical tumor suppressor role in the mammalian epidermis through direct regulation of PTEN and the PI3K/AKT/mTOR signaling pathway. GRHL3 is highly expressed in all tissues derived from the surface ectoderm, including the oral cavity, raising a question about its potential role in suppression of head and neck squamous cell carcinoma (HNSCC). Methods: We explored the tumor suppressor role of Grhl3 in HNSCC using a conditional knockout (Grhl3 a/-/K14Cre +) mouse line (n = 26) exposed to an oral chemical carcinogen. We defined the proto-oncogenic pathway activated in the HNSCC derived from these mice and assessed it in primary human HNSCC samples, normal oral epithelial cell lines carrying shRNA to GRHL3, and human HNSCC cell lines. Data were analyzed with two-sided chi square and Student s t tests. Results: Deletion of Grhl3 in oral epithelium in mice did not perturb PTEN/PI3K/AKT/mTOR signaling, but instead evoked loss of GSK3B expression, resulting in stabilization and accumulation of c-MYC and aggressive HNSCC. This molecular signature was also evident in a subset of primary human HNSCC and HNSCC cell lines. Loss of Gsk3b in mice, independent of Grhl3, predisposed to chemical-induced HNSCC. Restoration of GSK3B expression blocked proliferation of normal oral epithelial cell lines carrying shRNA to GRHL3 (cell no., Day 8: Scramble ctl, 616?21.8 x 103 vs GRHL3-kd, 1194?44 X 103, P
Original languageEnglish
Pages (from-to)1 - 13
Number of pages13
JournalJournal of the National Cancer Institute
Volume107
Issue number9
DOIs
Publication statusPublished - 2015

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