Li Yaoxu, Li Bing, Yang Kai, Zhu Lihua, Tang Hong, Huang Yinpei, Deng Jinhai, Duan Jun
Department of Stomatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, PR China; Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Wanzhou District, Chongqing, 404100, PR China.
Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Transl Oncol. 2025 Feb;52:102258. doi: 10.1016/j.tranon.2024.102258. Epub 2024 Dec 28.
The low expression of period circadian regulator 3 (PER3) in head and neck squamous cell carcinoma is closely correlated with tumor size and invasion depth. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) regulates epithelial-mesenchymal transition (EMT) transcription factors, activates EMT, and promotes tumor metastasis. Here, we investigated the role and molecular mechanism of PER3 in regulating HIF-1α and metastasis in oral squamous cell carcinoma (OSCC) by using bioinformatics analyses and in vitro and in vivo experiments. PER3 expression was decreased in OSCC, and PER3 expression was significantly negatively correlated with T stage, N stage, clinical classification, and survival time. PER3 overexpression inhibited, while PER3 knockdown prompted EMT and metastasis of OSCC cells. HIF-1α reversed the effects of alterations in PER3 expression on OSCC metastasis. Mechanistically, PER3 bound to HIF-1α via the Per-ARNT-Sim 1 domain and promoted its ubiquitination degradation. Hypermethylation at CpG site cg12258811 of PER3 promoter inhibited PER3 expression and prognosis of OSCC. Decitabine combined with LW6 upregulated PER3, downregulated HIF-1α, and inhibited lymph node metastasis of OSCC in nude mice. Our findings reveal the role and mechanism of HIF-1α regulation by PER3 and support the potential clinical application of targeting PER3 in treating OSCC metastasis.
周期昼夜节律调节因子3（PER3）在头颈部鳞状细胞癌中的低表达与肿瘤大小和浸润深度密切相关。缺氧诱导因子1α亚基（HIF-1α）调节上皮-间质转化（EMT）转录因子，激活EMT并促进肿瘤转移。在此，我们通过生物信息学分析以及体外和体内实验，研究了PER3在调节口腔鳞状细胞癌（OSCC）中HIF-1α和转移方面的作用及分子机制。OSCC中PER3表达降低，且PER3表达与T分期、N分期、临床分级及生存时间显著负相关。PER3过表达抑制OSCC细胞的EMT和转移，而PER3敲低则促进其发生。HIF-1α逆转了PER3表达改变对OSCC转移的影响。机制上，PER3通过Per-ARNT-Sim 1结构域与HIF-1α结合并促进其泛素化降解。PER3启动子的CpG位点cg12258811处的高甲基化抑制了OSCC的PER3表达和预后。地西他滨联合LW6上调PER3、下调HIF-1α，并抑制裸鼠中OSCC的淋巴结转移。我们的研究结果揭示了PER3调节HIF-1α的作用和机制，并支持靶向PER3在治疗OSCC转移中的潜在临床应用。
