J Cancer 2020; 11(12):3655-3666. doi:10.7150/jca.42771

Research Paper

Overexpression of the clock gene Per2 suppresses oral squamous cell carcinoma progression by activating autophagy via the PI3K/AKT/mTOR pathway

Huan Liu, Xiaobao Gong, Kai Yang

Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People's Republic of China

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Citation:
Liu H, Gong X, Yang K. Overexpression of the clock gene Per2 suppresses oral squamous cell carcinoma progression by activating autophagy via the PI3K/AKT/mTOR pathway. J Cancer 2020; 11(12):3655-3666. doi:10.7150/jca.42771. Available from http://www.jcancer.org/v11p3655.htm

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Abstract

The current studies reveal that the clock gene Per2 is expressed at lower levels in a variety of tumors and plays a significant tumor suppressor role. However, the biological functions and mechanism of Per2 in OSCC (OSCC: oral squamous cell carcinoma) remain unclear. In this study, OSCC cells with stable overexpression or silencing of Per2 were established to explore their biological functions and mechanism in vivo and in vitro. We discovered that the expression of Per2 decreases in OSCC cells. Overexpression of Per2 promoted autophagy and apoptosis in OSCC cells and inhibited proliferation. The opposite results were obtained in Per2-silenced OSCC cells. In Per2-overexpressing OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly reduced and the LC3B II/I ratio was significantly increased. In contrast, in Per2-silenced OSCC cells, the expression levels of PIK3CA, p-AKT, p-mTOR, p62 and Beclin1 were significantly enhanced and the LC3B II/I ratio was significantly reduced. When the AKT activator SC79 was added to Per2-overexpressing OSCC cells, the increased autophagy, apoptosis and decreased proliferation were significantly rescued. Furthermore, when autophinib, an autophagy inhibitor, was added to Per2-overexpressing OSCC cells, the decreased proliferation and increased apoptosis were significantly restored. An in vivo tumorigenesis assay also confirmed that overexpression of Per2 suppresses the growth of OSCC. In conclusion, our research results demonstrate that Per2 suppresses OSCC progression by motivating autophagy, as well as inhibiting cell proliferation and promoting apoptosis, which were mediated by autophagy, in a PI3K/AKT/mTOR pathway-dependent manner. Per2 could potentially be used as a valuable therapeutic marker for OSCC.

Keywords: clock genes, oral cancer, autophagy, carcinogenesis, Period 2