Wang Chun-I, Chen Cheng-Yi, Chen Ting-Wen, Cheng Chun-Chia, Hong Shu-Wen, Tsai Tsung-You, Chang Kai-Ping
Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan.
Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cell Death Discov. 2025 Jan 10;11(1):2. doi: 10.1038/s41420-025-02286-2.
Oral cavity squamous cell carcinoma (OSCC) represents the most prevalent malignancy among head and neck squamous cell carcinomas (HNSCCs). Standard treatment modalities include surgical resection combined with radiation and chemotherapy. However, locoregional failure remains a critical issue affecting the prognosis of OSCC patients, largely due to tumor resistance against radiation or chemotherapy. In this study, we established a gene database related to OSCC recurrence and identified PSMA2 as a novel molecule influencing prognosis in OSCC patients. An independent Taiwanese cohort confirmed that elevated PSMA2 transcript levels were associated with poorer prognosis and contributed to the chemo- and radioresistance phenotype in OSCC. Furthermore, we confirmed that PSMA2 regulates cell cycle, mitochondrial dysfunction, and mitophagy, thereby contributing to carcinogenesis and resistance. Notably, mitophagy inducer exhibit antitumor effects in PSMA2-overexpressing OSCC xenograft mouse model. Collectively, our results provide a mechanistic understanding of the atypical function of PSMA2 in promoting OSCC recurrence.
口腔鳞状细胞癌（OSCC）是头颈部鳞状细胞癌（HNSCC）中最常见的恶性肿瘤。标准治疗方式包括手术切除联合放疗和化疗。然而，局部区域复发仍然是影响OSCC患者预后的关键问题，这主要是由于肿瘤对放疗或化疗具有抗性。在本研究中，我们建立了一个与OSCC复发相关的基因数据库，并确定PSMA2是影响OSCC患者预后的一种新分子。一个独立的台湾队列证实，PSMA2转录水平升高与较差的预后相关，并导致OSCC出现化疗和放疗抗性表型。此外，我们证实PSMA2调节细胞周期、线粒体功能障碍和线粒体自噬，从而促进肿瘤发生和抗性。值得注意的是，线粒体自噬诱导剂在PSMA2过表达的OSCC异种移植小鼠模型中表现出抗肿瘤作用。总体而言，我们的结果为PSMA2促进OSCC复发的非典型功能提供了机制上的理解。
