Transforming Growth Factor-Beta 1 Activates Delta Np63/C-Myc To Promote Oral Squamous Cell Carcinoma

Objective. During the development of oral squamous cell carcinoma (OSCC), the transformed epithelial cells undergo increased proliferation resulting in tumor growth and invasion. Interestingly, throughout all phases of differentiation and progression to OSCC, transforming growth factor-beta 1 (TGF)-beta 1 induces cell cycle arrest or apoptosis; however, the role of TGF-beta 1 in promoting cancer cell proliferation has not been explored in detail. The purpose of this study was to identify the effect of TGF-beta 1 on OSCC cell proliferation.Study Design. Using both human OSCC samples and cell lines (UMSCC38 and UMSCC11B), we assessed protein, mRNA, gene expression, and protein-DNA interactions during OSCC progression.Results. Our results showed that TGF-beta 1 increased OSCC cell proliferation by upregulating the expression of Delta Np63 and cMyc oncogenes. Although the basal OSCC cell proliferation is sustained by activating Delta Np63, increased induction of c-Myc causes unregulated OSCC cell proliferation. Following induction of the cell cycle by Delta Np63 and c-Myc, cancer cells that halt c-Myc activity undergo epithelial mesenchymal transition or invasion while those that continue to express Delta Np63/c-Myc undergo unlimited progression through the cell cycle.Conclusions. OSCC proliferation is manifested by the induction of c-Myc in response to TGF-beta 1 signaling, which is essential for OSCC growth. Our data highlight the potential role of TGF-beta 1 in the induction of cancer progression and invasion of OSCC.