Loss of the clock gene Per1 promotes oral squamous cell carcinoma progression via the AKT/mTOR pathway

Current studies have shown that the clock gene Period 1 (Per1) is downregulated in various tumors and plays an important role in promoting tumor progression. However, the biological functions and mechanism of Per1 in tumors remain largely unknown. In this study, 86 specimens of oral squamous cell carcinoma (OSCC) tissues and adjacent noncancerous tissues were collected to determine the Per1 expression level and the clinical significance of Per1 expression. Per1 was stably inhibited or overexpressed in OSCC cells to investigate its function and mechanism in vitro and in vivo. We found that Per1 was remarkably downregulated in OSCC and that low Per1 expression was significantly associated with TNM clinical stage and poor prognosis of OSCC patients. Per1 overexpression in SCC15 OSCC cells (Per1-OE SCC15 cells) significantly promoted Autophagy and Apoptosis while inhibiting proliferation and the Akt/mTOR pathway. However, the results obtained in Per1-silenced TSCCA OSCC cells were opposite those obtained in Per1-OE SCC15 cells. After addition of the Akt Activator SC79 to Per1-OE SCC15 cells, the increased Autophagy and Apoptosis as well as decreased proliferation were remarkably rescued. Furthermore, increased Apoptosis was significantly rescued in Per1-OE SCC15 cells treated with the Autophagy Inhibitor autophinib. In vivo tumorigenicity assays also confirmed that Per1 overexpression suppressed tumor growth. Taken together, our findings demonstrate for the first time that Per1 promotes OSCC progression by inhibiting autophagy-mediated cell Apoptosis and enhancing cell proliferation in an Akt/mTOR pathway-dependent manner, and Per1 could be used as a valuable therapeutic target for OSCC.