Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cancer Sci. 2020 May;111(5):1542-1554. doi: 10.1111/cas.14362. Epub 2020 Mar 18.
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.
目前的研究表明，时钟基因 Period 1（Per1）在多种肿瘤中下调，在促进肿瘤进展中发挥重要作用。然而，Per1 在肿瘤中的生物学功能和机制在很大程度上仍然未知。在这项研究中，收集了 86 份口腔鳞状细胞癌（OSCC）组织和相邻非癌组织样本，以确定 Per1 的表达水平以及 Per1 表达的临床意义。在 OSCC 细胞中稳定抑制或过表达 Per1，以研究其在体外和体内的功能和机制。我们发现 Per1 在 OSCC 中明显下调，低表达 Per1 与 OSCC 患者的 TNM 临床分期和不良预后显著相关。在 SCC15 OSCC 细胞中过表达 Per1（Per1-OE SCC15 细胞）显著促进自噬和凋亡，同时抑制增殖和 AKT/mTOR 通路。然而，在沉默 Per1 的 TSCCA OSCC 细胞中得到的结果与在 Per1-OE SCC15 细胞中得到的结果相反。在用 AKT 激活剂 SC79 处理 Per1-OE SCC15 细胞后，增加的自噬和凋亡以及减少的增殖被显著挽救。此外，在用自噬抑制剂 autophinib 处理 Per1-OE SCC15 细胞后，增加的凋亡也得到了显著挽救。体内肿瘤发生实验也证实，过表达 Per1 抑制肿瘤生长。总之，我们的研究结果首次表明，Per1 通过抑制自噬介导的细胞凋亡和增强 AKT/mTOR 通路依赖性细胞增殖来促进 OSCC 进展，Per1 可以作为 OSCC 的一个有价值的治疗靶点。
