PRDX4通过靶向CALR/SERCA2相互作用减轻线粒体功能障碍，从而抑制喉鳞状细胞癌中的线粒体凋亡。
PRDX4 attenuates mitochondrial dysfunction by targeting CALR/SERCA2 interaction to suppress mitochondrial apoptosis in laryngeal squamous cell carcinoma.
文献信息
| PMID | 42906645 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Pengyan Liu |
| 作者单位 | Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. |
| 期刊 | Free radical biology & medicine |
| SCI 分区 | Q1 |
| IF | 8.8 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 咽喉科 |
中文摘要
背景： 癌细胞利用抗氧化防御系统对抗氧化应激，从而促进增殖和转移播散。过氧化物还原酶（PRDXs）是恶性肿瘤中常上调的主要抗氧化家族。过氧化物还原酶4（PRDX4）已被认为与肿瘤进展有关；然而，其在喉鳞状细胞癌（LSCC）中的功能作用和分子机制仍很大程度上不清楚。方法：在本研究中，我们通过慢病毒转导生成了PRDX4敲低或过表达的LSCC细胞系，随后进行了预后评估、RNA测序，以及对线粒体凋亡、线粒体形态和功能及氧化应激的系统评估，以表征PRDX4的生物学功能。在体内，建立了皮下异种移植小鼠模型以进一步验证其致瘤作用。结果：值得注意的是，PRDX4高表达预示LSCC患者预后不良。在机制上，PRDX4通过上调肌浆/内质网Ca2+ ATP酶2（SERCA2）促进LSCC进展。具体而言，PRDX4与钙网蛋白（CALR）结合，从而破坏CALR-SERCA2相互作用并导致SERCA2表达增加。因此，PRDX4介导的SERCA2上调减轻了线粒体钙超载并抑制了线粒体依赖性凋亡，最终驱动LSCC进展。结论：总之，这些发现阐明了PRDX4促进喉鳞状细胞癌进展的关键机制轴，突显了其作为预后生物标志物和治疗靶点的潜力。
英文摘要
Cancer cells exploit antioxidant defense systems to counteract oxidative stress, thereby facilitating proliferation and metastatic dissemination. Peroxiredoxins (PRDXs) represent a major antioxidant family frequently upregulated in malignancies. Peroxiredoxin 4 (PRDX4) has been implicated in tumor progression; however, its functional role and molecular mechanism in laryngeal squamous cell carcinoma (LSCC) remain largely elusive. In this study, we generated LSCC cell lines with PRDX4 knockdown or overexpression via lentiviral transduction, and subsequently performed prognostic evaluation, RNA sequencing, and systematic assessment of mitochondrial apoptosis, mitochondrial morphology and function, and oxidative stress to characterize the biological functions of PRDX4. In vivo, a subcutaneous xenograft mouse model was established to further validate its tumorigenic effects. Notably, high PRDX4 expression predicted an unfavorable prognosis in LSCC patients. Mechanistically, PRDX4 promoted LSCC progression through upregulation of sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2). Specifically, PRDX4 bound to calreticulin (CALR), thereby disrupting CALR-SERCA2 interaction and leading to increased SERCA2 expression. Consequently, PRDX4-mediated SERCA2 upregulation mitigated mitochondrial calcium overload and suppressed mitochondria-dependent apoptosis, ultimately driving LSCC progression. Collectively, these findings elucidate a key mechanistic axis through which PRDX4 promotes the progression of laryngeal squamous cell carcinoma, highlighting its potential as a prognostic biomarker and therapeutic target.